Inhibitors Of AKT Activity

ABSTRACT

The instant invention provides for substituted fused pyrimidine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.

BACKGROUND OF THE INVENTION

The present invention relates to substituted fused pyrimidine compoundswhich are inhibitors of the activity of one or more of the isoforms ofthe serine/threonine kinase, Akt (also known as PKB; hereinafterreferred to as “Akt”). The present invention also relates topharmaceutical compositions comprising such compounds and methods ofusing the instant compounds in the treatment of cancer.

Apoptosis (programmed cell death) plays essential roles in embryonicdevelopment and pathogenesis of various diseases, such as degenerativeneuronal diseases, cardiovascular diseases and cancer. Recent work hasled to the identification of various pro- and anti-apoptotic geneproducts that are involved in the regulation or execution of programmedcell death. Expression of anti-apoptotic genes, such as Bcl2 orBcl-x_(L), inhibits apoptotic cell death induced by various stimuli. Onthe other hand, expression of pro-apoptotic genes, such as Bax or Bad,leads to programmed cell death (Adams et al. Science, 281:1322-1326(1998)). The execution of programmed cell death is mediated by caspase-1related proteinases, including caspase-3, caspase-7, caspase-8 andcaspase-9 etc (Thornberry et al. Science, 281:1312-1316 (1998)).

The phosphatidylinositol 3′-OH kinase (PI3K)/Akt pathway appearsimportant for regulating cell survival/cell death (Kulik et al. Mol.Cell. Biol. 17:1595-1606 (1997); Franke et al, Cell, 88:435-437 (1997);Kauffmann-Zeh et al. Nature 385:544-548 (1997) Hemmings Science,275:628-630 (1997); Dudek et al., Science, 275:661-665 (1997)). Survivalfactors, such as platelet derived growth factor (PDGF), nerve growthfactor (NGF) and insulin-like growth factor-1 (IGF-1), promote cellsurvival under various conditions by inducing the activity of PI3K(Kulik et al. 1997, Hemmings 1997). Activated PI3K leads to theproduction of phosphatidylinositol (3,4,5)-triphosphate(PtdIns(3,4,5)-P3), which in turn binds to, and promotes the activationof, the serine/threonine kinase Akt, which contains a pleckstrinhomology (PH)-domain (Franke et al Cell, 81:727-736 (1995); HemmingsScience, 277:534 (1997); Downward, Curr. Opin. Cell Biol. 10:262-267(1998), Alessi et al., EMBO J. 15: 6541-6551 (1996)). Specificinhibitors of PI3K or dominant negative Akt mutants abolishsurvival-promoting activities of these growth factors or cytokines. Ithas been previously disclosed that inhibitors of PI3K (LY294002 orwortmannin) blocked the activation of Akt by upstream kinases. Inaddition, introduction of constitutively active PI3K or Akt mutantspromotes cell survival under conditions in which cells normally undergoapoptotic cell death (Kulik et al. 1997, Dudek et al. 1997).

Three members of the Akt subfamily of second-messenger regulatedserine/threonine protein kinases have been identified and termedAkt1/PKBct, Akt2/PKBβ, and Akt3/PKBγ (hereinafter referred to as “Akt1”,“Akt2” and “Akt3”), respectively. The isoforms are homologous,particularly in regions encoding the catalytic domains. Akts areactivated by phosphorylation events occurring in response to PI3Ksignaling. PI3K phosphorylates membrane inositol phospholipids,generating the second messengers phosphatidyl-inositol3,4,5-trisphos-phate and phosphatidylinositol 3,4-bisphosphate, whichhave been shown to bind to the PH domain of Akt. The current model ofAkt activation proposes recruitment of the enzyme to the membrane by3′-phosphorylated phosphoinositides, where phosphorylation of theregulatory-sites of Akt by the upstream kinases occurs (B. A. Hemmings,Science 275:628-630 (1997); B. A. Hemmings, Science 276:534 (1997); J.Downward, Science 279:673-674 (1998)).

Phosphorylation of Akt1 occurs on two regulatory sites, Thr³⁰⁸ in thecatalytic domain activation loop and on Ser⁴⁷³ near the carboxy terminus(D. R. Alessi et al. EMBO J. 15:6541-6551 (1996) and R. Meier et al. J.Biol. Chem. 272:30491-30497 (1997)). Equivalent regulatoryphosphorylation sites occur in Akt2 and Akt3. The upstream kinase, whichphosphorylates Akt at the activation loop site has been cloned andtermed 3′-phosphoinositide—dependent protein kinase 1 (PDK1). PDK1phosphorylates not only Akt, but also p70 ribosomal 56 kinase, p90RSK,serum and glucocorticoid-regulated kinase (SGK), and protein kinase C.The upstream kinase phosphorylating the regulatory site of Akt near thecarboxy terminus has not been identified yet, but recent reports imply arole for the integrin-linked kinase (ILK-1), a serine/threonine proteinkinase, or autophosphorylation.

Analysis of Akt levels in human tumors showed that Akt2 is overexpressedin a significant number of ovarian (J. Q. Cheng et al. Proc. Natl. Acad.Sci. U.S.A. 89:9267-9271 (1992)) and pancreatic cancers (J. Q. Cheng etal. Proc. Natl. Acad. Sci. U.S.A. 93:3636-3641 (1996)). Similarly, Akt3was found to be overexpressed in breast and prostate cancer cell lines(Nakatani et al. J. Biol. Chem. 274:21528-21532 (1999).

The tumor suppressor PTEN, a protein and lipid phosphatase thatspecifically removes the 3′ phosphate of PtdIns(3,4,5)-P3, is a negativeregulator of the PI3K/Akt pathway (Li et al. Science 275:1943-1947(1997), Stambolic et al. Cell 95:29-39 (1998), Sun et al. Proc. Natl.Acad. Sci. U.S.A. 96:6199-6204 (1999)). Germline mutations of PTEN areresponsible for human cancer syndromes such as Cowden disease (Liaw etal. Nature Genetics 16:64-67 (1997)). PTEN is deleted in a largepercentage of human tumors and tumor cell lines without functional PTENshow elevated levels of activated Akt (Li et al. supra, Guldberg et al.Cancer Research 57:3660-3663 (1997), Risinger et al. Cancer Research57:4736-4738 (1997)).

These observations demonstrate that the PI3K/Akt pathway plays importantroles for regulating cell survival or apoptosis in tumorigenesis.

Inhibition of Akt activation and activity can be achieved by inhibitingPI3K with inhibitors such as LY294002 and wortmannin. However, PI3Kinhibition has the potential to indiscriminately affect not just allthree Akt isozymes but also other PH domain-containing signalingmolecules that are dependent on PdtIns(3,4,5)—P3, such as the Tec familyof tyrosine kinases. Furthermore, it has been disclosed that Akt can beactivated by growth signals that are independent of PI3K.

Alternatively, Akt activity can be inhibited by blocking the activity ofthe upstream kinase PDK1. No specific PDK1 inhibitors have beendisclosed. Again, inhibition of PDK1 would result in inhibition ofmultiple protein kinases whose activities depend on PDK1, such asatypical PKC isoforms, SGK, and S6 kinases (Williams et al. Curr. Biol.10:439-448 (2000).

Inhibitors of Akt are known. WO2005/100344; WO2005/100356;WO2004/096135; WO2004/096129; WO2004/096130; WO2004/096131;WO2006/091395; WO2008/070134; WO2009/148916; WO2008/070016;WO2008/070041; WO2004/041162; WO2009/148887; WO2006/068796;WO2006/065601; WO2006/110638; WO02003/086394; WO2003/086403;WO2003/086404; WO2003/086279; WO2002/083139; WO2002/083675;WO2006/036395; WO2002/083138; WO2006/135627; and WO2002/083140. Thecompounds disclosed in these patent applications contain mono-, bi- andtri-cyclic core moieties.

Specific Akt inhibitors substituted with a methyl amine moiety areknown. WO2006/135627; WO2008/070041; WO2008/070016; WO2008/070134;WO2009/148887; and WO2009/148916.

The compounds of the instant invention contain a bi-cyclic core moietywith internal nitrogen atoms where the rings fuse which have not beenpreviously disclosed.

It is an object of the instant invention to provide novel compounds thatare inhibitors of Akt.

It is also an object of the present invention to provide pharmaceuticalcompositions that comprise the novel compounds that are inhibitors ofAkt.

It is also an object of the present invention to provide a method fortreating cancer that comprises administering such inhibitors of Aktactivity.

SUMMARY OF THE INVENTION

The instant invention provides for substituted fused pyrimidinecompounds that inhibit Akt activity. In particular, the compoundsdisclosed selectively inhibit one or two of the Akt isoforms. Theinvention also provides for compositions comprising such inhibitorycompounds and methods of inhibiting Akt activity by administering thecompound to a patient in need of treatment of cancer.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention are useful in the inhibition ofthe activity of the serine/threonine kinase Akt. In a first embodimentof this invention, the inhibitors of Akt activity are illustrated by theFormula A:

wherein:

A and B are independently selected from C or N, wherein at least one ofA and B is N;

J and K are independently selected from C or N, wherein J and K areoptionally substituted with R¹;

X, Y and Z are independently selected from C and N, wherein X, Y and Zare optionally substituted with R¹;

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is independently 0, 1, 2, 3,4 or 5;

Ring Q is selected from: (C₃-C₉)cycloalkyl, aryl, heteroaryl andheterocyclyl;

R¹ is independently selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl,(C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H, halo, OH,O_(b)(C₁-C₆)perfluoroalkyl, (C═O)_(a)NR⁷R⁸, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR⁷R⁸, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionallysubstituted with one or more substituents selected from R⁶;

R² is independently selected from: OH, halo and (C₁-C₄)alkyl, said alkylis optionally substituted with one or more substituents selected from OHand halo;

R³ and R^(3′) are independently selected from: H and (C₁-C₄)alkyl, saidalkyl is optionally substituted with one or more substituents selectedfrom OH, or R³ and R^(3′) can be taken together to form a(C₃-C₆)cycloalkyl, said cycloalkyl is optionally substituted with one ormore substituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CO₂H, halo,CN, OH and NH₂;

R⁶ is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, (C═O)_(a)O_(b) heterocyclyl, CO₂H, halo, CN, OH,O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁷R⁸, oxo, CHO, (N═O)R⁷R⁸,S(O)_(m)NR⁷R⁸, SH, S(O)_(m)—(C₁-C₁₀)alkyl or (C═O)_(a)O_(b)C₃-C₈cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl optionally substituted with one or more substituents selectedfrom R^(6a);

R^(6a) is selected from: (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,O_(a)(C₁-C₃)perfluoroalkyl, (C₀-C₆)alkylene-S(O)_(m)R^(a), SH, oxo, OH,halo, CN, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₆)cycloalkyl,(C₀-C₆)alkylene-aryl, (C₀-C₆)alkylene-heterocyclyl,(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a), (C₀-C₆)alkylene-CO₂R^(a), C(O)H,and (C₀-C₆)alkylene-CO₂H, said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, and heterocyclyl is optionally substituted with up to threesubstituents selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R^(b))₂;

R⁷ and R⁸ are independently selected from: H,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heterocyclyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, SH, SO₂R^(a), and (C═O)_(a)NR^(b)2, said alkyl,cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionallysubstituted with one or more substituents selected from R^(6a), or R⁷and R⁸ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 3-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocylcicor bicyclic heterocycle optionally substituted with one or moresubstituents selected from R^(6a);

R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl; and

R^(b) is independently: H, (C₁-C₆)alkyl, aryl, heterocyclyl,(C₃-C₆)cycloalkyl, (C═O)_(a)O_(b)(C₁-C₆)alkyl, or S(O)_(m)R^(a);

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a second embodiment of this invention, the inhibitors of Akt activityare illustrated by the Formula A, wherein:

is selected from:

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is independently 0, 1, 2, 3,4 or 5;

Ring Q is phenyl;

R¹ is independently selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H, halo, OH, O_(b)(C₁-C₆)perfluoroalkyl,(C═O)_(a)NR⁷R⁸, CN, (C═O)_(a)O_(b)(C₃-C₉)cycloalkyl, S(O)_(m)NR⁷R⁸, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionallysubstituted with one or more substituents selected from R⁶;

R² is independently selected from: OH, halo and (C₁-C₄)alkyl, said alkylis optionally substituted with one or more substituents selected from OHand halo;

R³ and R^(3′) are independently selected from: H and (C₁-C₄)alkyl, saidalkyl is optionally substituted with one or more substituents selectedfrom OH, or R³ and R^(3′) can be taken together to form a(C₃-C₆)cycloalkyl, said cycloalkyl is optionally substituted with one ormore substituents selected from OH and CH₃;

R⁶ is: (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl,C₂-C₁₀ alkynyl, (C═O)_(a)O_(b) heterocyclyl, CO₂H, halo, CN, OH,O_(b)C₁-C₆ perfluoroalkyl, O_(a)(C═O)_(b)NR⁷R⁸, oxo, CHO, (N═O)R⁷R⁸,S(O)_(m)NR⁷R⁸, SH, S(O)_(m)—(C₁-C₁₀)alkyl or (C═O)_(a)O_(b)C₃-C₉cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl optionally substituted with one or more substituents selectedfrom R^(6a);

R^(6a) is selected from: (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,O_(a)(C₁-C₃)perfluoroalkyl, (C₀-C₆)alkylene-S(O)_(m)R^(a), SH, oxo, OH,halo, CN, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₆)cycloalkyl,(C₀-C₆)allylene-aryl, (C₀-C₆)alkylene-heterocyclyl,(C₀-C₆)alkylene-N(R^(b))₂, C(O)R^(a), (C₀-C₆)alkylene-CO₂R^(a), C(O)H,and (C₀-C₆)alkylene-CO₂H, said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, and heterocyclyl is optionally substituted with up to threesubstituents selected from R^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN,O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R^(b))₂;

R⁷ and R⁸ are independently selected from: H,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heterocyclyl, (C₂-C₁₀)alkenyl,(C₂-C₁₀)alkynyl, SH, SO₂R^(a), and (C═O)_(a)NR^(b)2, said alkyl,cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionallysubstituted with one or more substituents selected from R^(6a), or R⁷and R⁸ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 3-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocylcicor bicyclic heterocycle optionally substituted with one or moresubstituents selected from R^(6a);

R^(a) is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, or heterocyclyl; and

R^(b) is independently: H, (C₁-C₆)alkyl, aryl, heterocyclyl,(C₃-C₆)cycloalkyl, (C═O)_(a)O_(b)(C₁-C₆)alkyl, or S(O)_(m)R^(a);

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a third embodiment of this invention, the inhibitors of Akt activityare illustrated by the Formula A, wherein:

is selected from

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is 0;

Ring Q is phenyl;

R¹ is independently selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,halo, OH, O_(b)(C₁-C₆)perfluoroalkyl, (C═O)_(a)NR⁷R⁸, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR⁷R⁸, SH,S(O)_(m)—(C₁-C₁₀)alkyl, said alkyl, alkenyl, alkynyl and cycloalkyl isoptionally substituted with one or more substituents selected from(C₁-C₆)alkyl, (C₁-C₆)alkoxy, CO₂H, halo, CN, OH and NH₂;

R³ and R^(3′) are taken together to form cyclobutyl, said cyclobutyl isoptionally substituted with one or more substituents selected from OHand CH₃; and

R⁷ and R⁸ are independently selected from: H and (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a fourth embodiment of this invention, the inhibitors of Akt activityare illustrated by the Formula B:

wherein,

A and B are independently selected from C or N, wherein at least one ofA and B is N;

J and K are independently selected from C or N, wherein J and K areoptionally substituted with R¹;

X, Y and Z are independently selected from C and N, wherein X, Y and Zare optionally substituted with R¹;

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2;

R¹ is independently selected from (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)(C₁-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₁-C₁₀)alkynyl,(C═O)_(a)O_(b)(C₃-C₁₀)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₁₀)alkyl,S(O)_(m)(C₁-C₁₀)alkenyl, S(O)_(m)(C₁-C₁₀)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R⁶;

R³ and R^(3′) are independently selected from H, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkenyl, (C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl, aryl, heteroaryl,heterocyclcyl, (C═O)NR⁷R⁸, halo, OH, CF₃, CO₂H, CN, and NH₂, said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl areoptionally substituted with one or more substituents selected from H,(C₁-C₄)alkyl, (C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₁₀)cycloalkyl, halo,OH, CF₃, CO₂H, CN, phenyl and NR⁷R⁸, or R³ and R^(3′) can be takentogether to form a (C₃-C₁₀)cycloalkyl, said cycloalkyl is optionallysubstituted with one or more substituents selected from H,(C₁-C₁₀)alkyl, (C₁-C₁₀)alkenyl, (C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl,aryl, heteroaryl, heterocyclcyl, (C═O)NR⁷R⁸, halo, OH, CF₃, CO₂H, CN,phenyl and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are further optionally substituted with oneor more substituents selected from H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl,(C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H, CN, phenyl andNR⁷R⁸;

R⁶ is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl,S(O)_(m)(C₁-C₄)alkenyl, S(O)_(m)(C₁-C₄)alkynyl,S(O)_(m)(C₃-C₉)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a);

R^(6a) is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂;

R⁷ and R⁸ are independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₉)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, N(R^(b))₂, (C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)N(R^(b))₂,S(O)_(m)(C₁-C₆)alkyl, S(O)_(m)(C₁-C₆)alkenyl, S(O)_(m)(C₁-C₆)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a), or R⁷ and R⁸ can be taken together toform a (C₃-C₁₀)cycloalkyl, said cycloalkyl is optionally substitutedwith one or more substituents selected from H, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkenyl, (C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl, aryl, heteroaryl,heterocyclcyl, (C═O)NR⁷R⁸, halo, OH, CF₃, CO₂H, CN, and NR⁷R⁸; and

R^(b) is independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl areoptionally substituted with one or more substituents selected from(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, halo, OH, CF₃, CO₂H, CN,phenyl and NH₂;

or a tautomer thereof;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a fifth embodiment of this invention, the inhibitors of Akt activityare illustrated by the Formula B, wherein,

is selected from:

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2;

R¹ is independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl,S(O)_(m)(C₁-C₄)alkenyl, S(O)_(m)(C₁-C₄)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R⁶;

R³ and R^(3′) are independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H,CN, phenyl and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl and phenylare optionally substituted with one or more substituents selected fromH, (C₁-C₄)alkyl, (C₁-C₄) alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂, or R³ and R^(3′) can be takentogether to form a (C₃-C₅)cycloalkyl, said cycloalkyl is optionallysubstituted with one or more substituents selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H,CN, phenyl and NH₂;

R⁶ is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl,S(O)_(m)(C₁-C₄)alkenyl, S(O)_(m)(C₁-C₄)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a);

R^(6a) is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₉)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂;

R⁷ and R⁸ are independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, N(R^(b))₂, (C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)N(R^(b))₂,S(O)_(m)(C₁-C₆)alkyl, S(O)_(m)(C₁-C₆)alkenyl, S(O)_(m)(C₁-C₆)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a); and

R^(b) is independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl areoptionally substituted with one or more substituents selected from(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, halo, OH, CF₃, CO₂H, CN,phenyl and NH₂;

or a tautomer thereof;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a sixth embodiment of this invention, the inhibitors of Akt activityare illustrated by the Formula B, wherein:

is selected from

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0,1, 2 or 3;

R¹ is independently selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl,S(O)_(m)(C₁-C₄)alkenyl, S(O)_(m)(C₁-C₄)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R⁶;

R³ and R^(3′) are independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H,CN, phenyl and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl and phenylare optionally substituted with one or more substituents selected fromH, (C₁-C₄)alkyl, (C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂, or R³ and R^(3′) can be takentogether to form a (C₃-C₅)cycloalkyl, said cycloalkyl is optionallysubstituted with one or more substituents selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H,CN, phenyl and NH₂;

R⁶ is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl,S(O)_(m)(C₁-C₄)alkenyl, S(O)_(m)(C₁-C₄)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a);

R^(6a) is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂;

R⁷ and R⁸ are independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, N(R^(b))₂, (C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)N(R^(b))₂,S(O)_(m)(C₁-C₆)alkyl, S(O)_(m)(C₁-C₆)alkenyl, S(O)_(m)(C₁-C₆)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a); and

R^(b) is independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl areoptionally substituted with one or more substituents selected from(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, halo, OH, CF₃, CO₂H, CN,phenyl and NH₂;

or a tautomer thereof;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a seventh embodiment of this invention, the inhibitors of Aktactivity are illustrated by the Formula B, wherein:

is selected from

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0, 1 or 2;

R¹ is independently selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C₁-C₆)alkenyl, (C₃-C₈)cycloalkyl, O_(b)-aryl, O_(b)-heteroaryl,(C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃, CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸,S(O)_(m)(C₁-C₄)alkyl, said alkyl, alkenyl, cycloalkyl, aryl, heteroaryland heterocyclyl are optionally substituted with one or moresubstituents selected from R⁶;

R³ and R^(3′) are H, or R³ and R^(3′) can be taken together to formcyclobutyl, said cyclobutyl is optionally substituted with one or moresubstituents selected from H, OH, methyl and cyclopropyl;

R⁶ is selected from O_(b)(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, O_(b)-aryl,halo, OH, CF₃, NR⁷R⁸, said alkyl and cycloalkyl are optionallysubstituted with one or more substituents selected from R^(6a);

R^(6a) is selected from O_(b)(C₁-C₆)alkyl, aryl, OH and NH₂, said alkyland aryl are optionally substituted with one or more substituentsselected from halo;

R⁷ and R⁸ are independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)(C₃-C₈)cycloalkyl, (C═O)_(a)-aryl, heterocyclyl,(C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)(C₁-C₆)alkyl, and S(O)_(m)-aryl,said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionallysubstituted with one or more substituents selected from R^(6a); and

R^(b) is independently selected from H, (C₁-C₆)alkyl and aryl;

or a tautomer thereof;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

Specific compounds of the instant invention include:

-   1-[4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine    (A-1);-   1-[4-(2-isopropyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (B-1);-   1-[4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (C-1);-   1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine    (D);-   3-amino-3-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]-1-methylcyclobutanol    (E);-   3-amino-1-methyl-3-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanol    (F);-   1-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine    (G);-   3-amino-1-methyl-3-[4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol    (H);-   3-amino-1-methyl-3-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol    (I);-   1-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (J);-   1-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (K);-   3-amino-1-methyl-3-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol    (L);-   1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]methanamine    (M);-   1-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]methanamine (N);    and-   1-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]methanamine    (O);    or a pharmaceutically acceptable salt or stereoisomer thereof.

Specific compounds of the instant invention include:

-   1-[4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine    (A-1);-   1-[4-(2-isopropyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (B-1);-   1-[4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (C-1);-   1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine    (D);-   3-amino-3-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]-1-methylcyclobutanol    (E);-   3-amino-1-methyl-3-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanol    (F);-   1-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine    (G);-   3-amino-1-methyl-3-[4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol    (H);-   3-amino-1-methyl-3-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol    (1);-   1-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (J);-   1-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine    (K);-   3-amino-1-methyl-3-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol    (L);-   1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]methanamine    (M);-   1-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]methanamine (N);-   1-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]methanamine    (O);-   4-(6-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-benzylamine (3-6);-   3-Amino-1-cyclopropyl-3-[4-(6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutanol    (3-7);-   4-(6-Phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-benzylamine (3-8);-   1-[4-(6-Phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (4-2);-   1-[4-(3-Bromo-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (4-4);-   1-[4-(6-Phenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (4-6);-   1-{4-[3-(2-Methoxy-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine    (4-8);-   7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carbonitrile    (4-10);-   7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carboxylic    acid amide (4-11);-   1-[4-(3-Chloro-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (4-14);-   1-[4-(3-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (4-15);-   1-{4-[3-(2-Cyclopropyl-vinyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine    (4-16);-   1-[4-(2,6-Diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-3);-   1-[4-(3-Bromo-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-5);-   1-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine    (5-7);-   1-[4-(2,6-Diphenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-9);-   1-[4-(2-Ethyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-11);-   1-[4-(6-Phenyl-2-trifluoromethyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-12);-   7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic    acid ethyl ester (5-13);-   7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic    acid (5-14);-   7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic    acid methyl ester (5-15);-   1-{4-[2-(4-Fluoro-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine    (5-16);-   1-[4-(6-Phenyl-2-p-tolyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-17);-   1-[4-(3-Bromo-6-phenyl-2-trifluoromethyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-18);-   1-[4-(3-Methyl-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-19);-   1-[4-(2,3,6-Triphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-20);-   1-[4-(3-Cyclopropyl-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-21);-   1-{4-[2,6-Diphenyl-3-(2,3,4-trifluoro-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine    (5-22);-   1-[4-(2,6-Diphenyl-3-propenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine    (5-23);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine    (6-2);-   N-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-acetamide    (6-4);-   1-[4-(2,6-Diphenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-7);-   1-[4-(2-Phenoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-9);-   1-[4-(2-Morpholin-4-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-10);-   1-[4-(6-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-11);-   1-[4-(2-Methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-12);-   Ethanesulfonic    acid{5-[4-(1-amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-amide    (6-13);-   N-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-benzenesulfonamide    (6-14);-   N-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-benzamide    (6-15);-   Cyclopropanecarboxylic    acid{5-[4-(1-amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-amide    (6-16);-   1-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-3-phenyl-urea    (6-17);-   1-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-3-phenyl-thiourea    (6-18);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazzolo[1,5-a]pyrimidin-2-yl}-carbamic    acid ethyl ester (6-19);-   1-{4-[2-(6-Methoxy-pyridin-2-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-20);-   1-[4-(6-Phenyl-2-pyrazin-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-21);-   1-{4-[2-(2,3-Dimethyl-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-22);-   1-{4-[2-(3,4-Difluoro-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-23);-   1-{4-[2-(5-Fluoro-2-methyl-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-24);-   1-[4-(6-Phenyl-2-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-25);-   4-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-phenylamine    (6-26);-   1-[4-(6-Phenyl-2-p-tolyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-27);-   1-{4-[2-(4-Methoxy-phenyl)-6-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-28);-   1-[4-(6-Phenyl-2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-29);-   1-{4-[2-(2-Methoxy-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-30);-   1-{4-[2-(3-Chloro-4-fluoro-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-31);-   1-{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-32);-   1-{4-[6-Phenyl-2-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-33);-   1-{4-[2-(2,4-Dimethoxy-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-34);-   1-[4-(2-Furan-3-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-35);-   1-[4-(6-Phenyl-2-thiophen-3-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-36);-   1-[4-(6-Phenyl-2-thiophen-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-37);-   1-{4-[2-(6-Methoxy-naphthalen-2-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-38);-   1-[4-(2-Dibenzofuran-4-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-39);-   4-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-phenol    (6-40);-   1-[4-(6-Phenyl-2-m-tolyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-41);-   1-{4-[2-(4-Phenoxy-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-42);-   1-[4-(2-Biphenyl-2-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-43);-   1-[4-(2-Benzothiazol-2-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-44);-   1-[4-(6-Phenyl-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-45);-   1-[4-(6-Phenyl-2-thiazol-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-46);-   1-{4-[6-Phenyl-2-(pyridin-4-yloxy)-[1,2,4]triazolo[1,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-47);-   1-[4-(2-Methoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-48);-   1-[4-(2-Phenoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-49);-   1-[4-(2-Methylsulfanyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-50);-   1-{4-[2-(Naphthalen-2-yloxy)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-51);-   1-{4-[2-(Biphenyl-2-yloxy)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-52);-   1-{4-[2-(Isoquinolin-7-yloxy)-6-phenyl-[1,2,4]triazlo[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-53);-   1-{4-[2-(4-Phenoxy-phenoxy)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-54);-   1-{4-[2-(3,4-Dihydro-2H-quinolin-1-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-55);-   1-{4-[2-(2,3-Dihydro-indol-1-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (6-56);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-methyl-amine    (6-57);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-dimethyl-amine    (6-58);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-pyridin-3-yl-amine    (6-59);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-diethyl-amine    (6-60);-   N1-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-ethane-1,2-diamine    (6-61);-   2-({5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-methyl-amino)-ethanol    (6-62);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-benzyl-methyl-amine    (6-63);-   1-[4-(2-{4-[Bis-(4-chloro-phenyl)-methyl]-piperazin-1-yl}-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (6-64);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-methyl-phenyl-amine    (6-65);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-(2-methoxy-ethyl)-amine    (6-66);-   3-Amino-3-[4-(2,6-diphenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol    (7-2);-   3-Amino-1-methyl-3-[4-(6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutanol    (7-3);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid methyl ester (8-2);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid (8-4);-   2-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-propan-2-ol    (8-6);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid methylamide (8-8);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-diphenyl-methanol    (8-9);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid amide (8-10);-   {5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-morpholin-4-yl-methanone    (8-11);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid phenethyl-amide (8-12);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid diethylamide (8-13);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid phenylamide (8-14);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid benzyl-methyl-amide (8-15);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid methoxy-methyl-amide (8-16);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic    acid methyl-phenyl-amide (8-17);-   1-[4-(2,6-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-2);-   1-[4-(2,3,6-Triphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-4);-   1-[4-(2,3,6-Triphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-6);-   1-[4-(6-Phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-8);-   1-[4-(2-Methyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-9);-   5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-pyrazolo[1,5-a]pyrimidin-2-ol    (9-10);-   1-[4-(6-Phenyl-2-p-tolyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-11);-   1-{4-[2-(4-Methoxy-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-12);-   1-[4-(6-Phenyl-2-o-tolyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-13);-   1-{4-[2-(4-Chloro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-14);-   1-{4-[2-(3-Fluoro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-15);-   1-{4-[6-Phenyl-2-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-16);-   1-{4-[2-(4-Fluoro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-17);-   1-[4-(3-Chloro-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-18);-   1-[4-(3-Bromo-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-19);-   1-[4-(2,6-Diphenyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-20);-   1-[4-(3-Methyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-21);-   1-{4-[3-(2,4-Difluoro-phenyl)-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-22);-   1-[4-(3-Methyl-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-23);-   1-[4-(3,6-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-24);-   1-[4-(6-Phenyl-3-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-25);-   1-{4-[3-(4-Methoxy-phenyl)-2-methyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-26);-   1-{4-[3-(2-Methoxy-pyrimidin-5-yl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-27);-   1-{4-[6-Phenyl-3-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-28);-   1-[4-(3-Naphthalen-1-yl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine    (9-29);-   1-{4-[3-(2-Fluoro-5-trifluoromethyl-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-30);-   1-{4-[3-(3-Chloro-4-fluoro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-31);-   1-{4-[3-(3-Fluoro-5-isopropoxy-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-32);-   1-{4-[6-Phenyl-3-(2,3,4-trifluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine    (9-33);-   3-Amino-3-[4-(2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol    (10-2);-   3-Amino-3-[4-(3-bromo-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol    (10-4);-   3-Amino-1-methyl-3-[4-(3-methyl-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutanol    (10-6);-   3-Amino-1-methyl-3-[4-(2,6-phenyl-2-o-tolyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutanol    (10-7);-   3-Amino-3-{4-[2-(4-fluoro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-1-methyl-cyclobutanol    (10-8);-   3-Amino-3-[4-(2,6-diphenyl-3-pyridin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol    (10-9);-   3-Amino-3-{4-[3-(3-amino-phenyl)-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-1-methyl-cyclobutanol    (10-10);-   3-Amino-3-[4-(2,6-diphenyl-3-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol    (10-11); and-   3-Amino-3-{4-[3-(2-amino-pyrimidin-5-yl)-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-1-methyl-cyclobutanol    (10-12);    or a tautomer thereof;    or a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers; all such stereoisomers beingincluded in the present invention.

In addition, the compounds disclosed herein may exist as tautomers andboth tautomeric forms are intended to be encompassed by the scope of theinvention, even though only one tautomeric structure is depicted. Forexample the following is within the scope of the instant invention:

In particular, compounds disclosed in Formulas A, B and C may exist inthe keto form (i.e. oxo substituent). An oxo group is included in theinstant invention and where appropriate is a member of the substituentlist (R¹, R², R³, R^(3′), R^(3″), R⁶, R⁷, R⁸, R^(a), R^(b)). Tetrazolesexist as a mixture of 1H/2H tautomers. The tautomeric forms of thetetrazol moiety are also within the scope of the instant invention.

This invention is also intended to encompass pro-drugs of the compoundsdisclosed herein. A prodrug of any of the compounds can be made usingwell known pharmacological techniques.

When any variable (e.g. R¹, etc.) occurs more than one time in anyconstituent, its definition on each occurrence is independent at everyother occurrence. Also, combinations of substituents and variables arepermissible only if such combinations result in stable compounds.

Lines drawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is bicyclic, it is intended that the bond be attachedto any of the suitable atoms on either ring of the bicyclic moiety.

It is understood that one or more silicon (Si) atoms can be incorporatedinto the compounds of the instant invention in place of one or morecarbon atoms by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art from readily available starting materials.Carbon and silicon differ in their covalent radius leading todifferences in bond distance and the steric arrangement when comparinganalogous C-element and Si-element bonds. These differences lead tosubtle changes in the size and shape of silicon-containing compoundswhen compared to carbon. One of ordinary skill in the art wouldunderstand that size and shape differences can lead to subtle ordramatic changes in potency, solubility, lack of off target activity,packaging properties, and so on. (Diass, J. O. et al. Organometallics(2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & MedicinalChemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to four substituents, and the more preferred embodimentwill have from zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in“(C₁-C₁₀)alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 carbons in a linear or branched arrange-ment. For example,“(C₁-C₁₀)alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,and so on.

The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example,“cycloalkyl” includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“(C₂-C₁₀)alkenyl” means an alkenyl radical having from 2 to 10 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “(C₂-C₁₀)alkynyl” means an alkynyl radical having from 2to 10 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydro-naphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively. Suchheteroaryl moieties for substituent Q include but are not limited to:2-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,1-isoquinolinyl, 3-isoquinolinyl and 4-isoquinolinyl.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzoimidazolonyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro (Cl), fluoro (F), bromo (Br) andiodo (I).

In an embodiment of Formula A, X, Y and Z are independently selectedfrom C and N, wherein X, Y and Z are optionally substituted with R¹.

In an embodiment of Formula A, the moiety illustrated by the formula:

includes the following structures:

In an embodiment, Ring Q is selected from: phenyl and heterocyclyl.

In yet another embodiment, Ring Q is phenyl.

In an embodiment, p is independently 0, 1, 2 or 3.

In a further embodiment, p is independently 0, 1 or 2.

In another embodiment, p is independently 1.

In another embodiment, p is 0.

In an embodiment, R¹ is selected from: oxo, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₆)alkenyl, (C═O)_(a)O_(b)(C₂-C₆)alkynyl, CO₂H, halo, OH, O_(b)(C₁-C₆)perfluoroalkyl,(C═O)_(a)NH₂, CN, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)₂NH₂, SH,S(O)₂—(C₁-C₆)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl, aryl,alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substitutedwith halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-NH₂, OH, O(C₁-C₆)alkyl.

In another embodiment, R¹ is selected from: oxo,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, CO₂H, halo, OH, CN, (C₁-C₆)alkoxy,S(O)₂NH₂, SH, S(O)₂—(C₁-C₆)alkyl, O(C═O)(C₁-C₆)alkyl and NH₂, said alkylis optionally substituted with halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-NH₂, OH,O(C₁-C₆)alkyl.

In another embodiment, R¹ is selected from: oxo, NH₂, OH, SH,O_(a)(C₁-C₆)alkyl, said alkyl is optionally substituted with halo, NH₂,OH, O(C₁-C₆)alkyl.

In another embodiment, when R¹ is aryl, said aryl is phenyl.

In an embodiment, R³ and R^(3′) are independently selected from: H and(C₁-C₄)alkyl, said alkyl is optionally substituted with one or moresubstituents selected from OH, or R³ and R^(3′) can be taken together toform cyclopropyl, cyclobutyl, cyclopentyl or cyclo hexyl, saidcyclo-moiety is optionally substituted with one or more substituentsselected from OH and CH₃.

In another embodiment, R³ and R^(3′) are independently selected from: Hand CH₃, or R³ and R^(3′) can be taken together to form cyclobutyl, saidcyclobutyl is optionally substituted with one or more substituentsselected from OH and CH₃.

In another embodiment, R³ and R^(3′) are taken together to formcyclobutyl, said cyclobutyl is optionally substituted with one or moresubstituents selected from OH and CH₃.

In an embodiment of Formula C, R^(3′) and R^(3″) are independently H,OH, cyclopropyl and CH₃.

In an embodiment R² is independently selected from H, OH, halo,O(C₁-C₃)alkyl and (C₁-C₃)alkyl.

In an embodiment R² is H.

In an embodiment, R^(a) is (C₁-C₆)alkyl.

In an embodiment R^(b) is independently selected from H and(C₁-C₆)alkyl.

In another embodiment of Formula A, Ring Q is phenyl; R³ and R^(3′) aretaken together to form cyclobutyl, which is optionally substituted withOH and CH₃; R¹ is selected from: H, heterocyclyl, (C₃-C₆)cycloalkyl, OH,(C₁-C₆)alkyl, NH(C₁-C₆)alkyl, NH-heterocyclyl, NH-cycloalkyl, saidheterocyclyl, cycloalkyl and alkyl is optionally substituted with: halo,(C₁-C₆)alkyl, (C₁-C₆)alkyl-NH₂, OH, O(C₁-C₆)alkyl; and R² is H or F.

In another embodiment of Formula A, Ring Q is phenyl; p is 0; R³ andR^(3′) are taken together to form cyclobutyl, which is optionallysubstituted with OH and CH₃; and R¹ is selected from: H, heterocyclyl,(C₃-C₆)cycloalkyl, OH, (C₁-C₆)alkyl, NH(C₁-C₆)alkyl, NH-heterocyclyl,NH-cycloalkyl, said heterocyclyl, cycloalkyl and alkyl is optionallysubstituted with: halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-NH₂, OH,O(C₁-C₆)alkyl.

In an aspect of all embodiments of Formulas A and B, R³ and R^(3′) areH, or R³ and R^(3′) are taken together to form cyclobutyl, saidcyclobutyl is optionally substituted with one or more substituentsselected from OH, CH₃ and cyclopropyl.

In an aspect of all embodiments of Formulas A and B, R³ and R^(3′) areindependently selected from H, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkenyl,(C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl, aryl, heteroaryl, heterocyclcyl,(C═O)NR⁷R⁸, halo, OH, CF₃, CO₂H, CN, and NH₂, said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionallysubstituted with one or more substituents selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₁₀)cycloalkyl, halo, OH, CF₃, CO₂H,CN, phenyl and NR⁷R⁸, or R³ and R^(3′) can be taken together to form a(C₃-C₁₀)cycloalkyl, said cycloalkyl is optionally substituted with oneor more substituents selected from H, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkenyl,(C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl, aryl, heteroaryl, heterocyclcyl,(C═O)NR⁷R⁸, halo, OH, CF₃, CO₂H, CN, phenyl and NH₂, said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl arefurther optionally substituted with one or more substituents selectedfrom H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl,halo, OH, CF₃, CO₂H, CN, phenyl and NR⁷R⁸.

In an aspect of all embodiments of Formulas A and B, R⁶ is selected fromO_(b)(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, O_(b)-aryl, halo, OH, CF₃, NR⁷R⁸,said alkyl and cycloalkyl are optionally substituted with one or moresubstituents selected from R^(6a).

In an aspect of all embodiments of Formulas A and B, R^(6a) is selectedfrom O_(b)(C₁-C₆)alkyl, aryl, OH and NH₂, said alkyl and aryl areoptionally substituted with one or more substituents selected from halo.

In an aspect of all embodiments of Formulas A and B, R⁷ and R⁸ areindependently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)(C₃-C₉)cycloalkyl, (C═O)_(a)-aryl, heterocyclyl,(C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)(C₁-C₆)alkyl, and S(O)_(m)-aryl,said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionallysubstituted with one or more substituents selected from R^(6a).

In an embodiment of Formula B, R⁷ and R⁸ are independently selected fromH, (C₁-C₄)alkyl and phenyl.

In an embodiment of Formula B, R^(b) is independently selected from H,(C₁-C₄)alkyl, and phenyl.

Included in the instant invention is the free form of compounds ofFormula A, as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the isolated specific compoundsexemplified herein are the protonated salts of amine compounds. The term“free form” refers to the amine compounds in non-salt form. Theencompassed pharmaceutically acceptable salts not only include theisolated salts exemplified for the specific compounds described herein,but also all the typical pharmaceutically acceptable salts of the freeform of compounds of Formula A. The free form of the specific saltcompounds described may be isolated using techniques known in the art.For example, the free form may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous NaOH,potassium carbonate, ammonia and sodium bicarbonate. The free forms maydiffer from their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise pharmaceutically equivalent to their respective freeforms for purposes of the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric

and the like, as well as salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,trifluoroacetic (TFA) and the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

UTILITY

The compounds of the instant invention are inhibitors of the activity ofAkt and are thus useful in the treatment of cancer, in particularcancers associated with irregularities in the activity of Akt anddownstream cellular targets of Akt. Such cancers include, but are notlimited to, ovarian, pancreatic, breast and prostate cancer, as well ascancers (including glioblastoma) where the tumor suppressor PTEN ismutated (Cheng et al., Proc. Natl. Acad. Sci. (1992) 89:9267-9271; Chenget al., Proc. Natl. Acad. Sci. (1996) 93:3636-3641; Bellacosa et al.,Int. J. Cancer (1995) 64:280-285; Nakatani et al., J. Biol. Chem. (1999)274:21528-21532; Graft, Expert. Opin. Ther. Targets (2002) 6(1):103-113;and Yamada and Araki, J. Cell Science. (2001) 114:2375-2382; Mischel andCloughesy, Brain Pathol. (2003) 13(1):52-61).

The compounds, compositions and methods provided herein are particularlydeemed useful for the treatment of cancer. Cancers that may be treatedby the compounds, compositions and methods of the invention include, butare not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: non-small ceel lung, bronchogenic carcinoma (squamouscell, undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colorectal, rectal; Genitourinary tract: kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.Thus, the term “cancerous cell” as provided herein, includes a cellafflicted by any one of the above-identified conditions.

Cancers that may be treated by the compounds, compositions and methodsof the invention include, but are not limited to: breast, prostate,colon, colorectal, lung, non-small cell lung, brain, testicular,stomach, pancrease, skin, small intestine, large intestine, throat, headand neck, oral, bone, liver, bladder, kidney, thyroid and blood.

Cancers that may be treated by the compounds, compositions and methodsof the invention include: breast, prostate, colon, ovarian, colorectal,lung and non-small cell lung.

Cancers that may be treated by the compounds, compositions and methodsof the invention include: breast, colon, (colorectal) and lung(non-small cell lung).

Cancers that may be treated by the compounds, compositions and methodsof the invention include: lymphoma and leukemia.

The compounds of the instant invention are useful for the treatment ofbreast cancer.

The compounds of the instant invention are useful for the treatment ofprostate cancer.

Akt signaling regulates multiple critical steps in angiogenesis.Shiojima and Walsh, Circ. Res. (2002) 90:1243-1250. The utility ofangiogenesis inhibitors in the treatment of cancer is known in theliterature, see J. Rak et al. Cancer Research, 55:4575-4580, 1995 andDredge et al., Expert Opin. Biol. Ther. (2002) 2(8):953-966, forexample. The role of angiogenesis in cancer has been shown in numeroustypes of cancer and tissues: breast carcinoma (G. Gasparini and A. L.Harris, J. Clin. Oncol, 1995, 13:765-782; M. Toi et al., Japan. J.Cancer Res., 1994, 85:1045-1049); bladder carcinomas (A. J. Dickinson etal., Br. J. Urol., 1994, 74:762-766); colon carcinomas (L. M. Ellis etal., Surgery, 1996, 120(5):871-878); and oral cavity tumors (J. K.Williams et al., Am. J. Surg., 1994, 168:373-380). Other cancersinclude, advanced tumors, hairy cell leukemia, melanoma, advanced headand neck, metastatic renal cell, non-Hodgkin's lymphoma, metastaticbreast, breast adenocarcinoma, advanced melanoma, pancreatic, gastric,glioblastoma, lung, ovarian, non-small cell lung, prostate, small celllung, renal cell carcinoma, various solid tumors, multiple myeloma,metastatic prostate, malignant glioma, renal cancer, lymphoma,refractory metastatic disease, refractory multiple myeloma, cervicalcancer, Kaposi's sarcoma, recurrent anaplastic glioma, and metastaticcolon cancer (Dredge et al., Expert Opin. Biol. Ther. (2002)2(8):953-966). Thus, the Akt inhibitors disclosed in the instantapplication are also useful in the treatment of these angiogenesisrelated cancers.

Tumors which have undergone neovascularization show an increasedpotential for metastasis. In fact, angiogenesis is essential for tumorgrowth and metastasis. (S. P. Cunningham, et al., Can. Research, 61:3206-3211 (2001)). The Akt inhibitors disclosed in the presentapplication are therefore also useful to prevent or decrease tumor cellmetastasis.

Further included within the scope of the invention is a method oftreating or preventing a disease in which angiogenesis is implicated,which is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention. Ocular neovascular diseases are an example ofconditions where much of the resulting tissue damage can be attributedto aberrant infiltration of blood vessels in the eye (see WO 00/30651,published 2 Jun. 2000). The undesirable infiltration can be triggered byischemic retinopathy, such as that resulting from diabetic retinopathy,retinopathy of prematurity, retinal vein occlusions, etc., or bydegenerative diseases, such as the choroidal neovascularization observedin age-related macular degeneration. Inhibiting the growth of bloodvessels by administration of the present compounds would thereforeprevent the infiltration of blood vessels and prevent or treat diseaseswhere angiogenesis is implicated, such as ocular diseases like retinalvascularization, diabetic retinopathy, age-related macular degeneration,and the like.

Further included within the scope of the invention is a method oftreating or preventing a non-malignant disease in which angiogenesis isimplicated, including but not limited to: ocular diseases (such as,retinal vascularization, diabetic retinopathy and age-related maculardegeneration), atherosclerosis, arthritis, psoriasis, obesity andAlzheimer's disease (Dredge et al., Expert Opin. Biol. Ther. (2002)2(8):953-966). In another embodiment, a method of treating or preventinga disease in which angiogenesis is implicated includes: ocular diseases(such as, retinal vascularization, diabetic retinopathy and age-relatedmacular degeneration), atherosclerosis, arthritis and psoriasis.

Further included within the scope of the invention is a method oftreating hyperproliferative disorders such as restenosis, inflammation,autoimmune diseases and allergy/asthma.

Further included within the scope of the instant invention is the use ofthe instant compounds to coat stents and therefore the use of theinstant compounds on coated stents for the treatment and/or preventionof restenosis (WO03/032809).

Further included within the scope of the instant invention is the use ofthe instant compounds for the treatment and/or prevention ofosteoarthritis (WO03/035048).

Further included within the scope of the invention is a method oftreating hyperinsulinism.

The compounds of the invention are also useful in preparing a medicamentthat is useful in treating the diseases described above, in particularcancer.

In an embodiment of the invention, the instant compound is a selectiveinhibitor whose inhibitory efficacy is dependent on the PH domain. Inthis embodiment, the compound exhibits a decrease in in vitro inhibitoryactivity or no in vitro inhibitory activity against truncated Aktproteins lacking the PH domain.

In a further embodiment, the instant compound is selected from the groupof a selective inhibitor of Akt1, a selective inhibitor of Akt2 and aselective inhibitor of both Akt1 and Akt2.

In another embodiment, the instant compound is selected from the groupof a selective inhibitor of Akt1, a selective inhibitor of Akt2, aselective inhibitor of Akt3 and a selective inhibitor of two of thethree Akt isoforms.

In another embodiment, the instant compound is a selective inhibitor ofall three Akt isoforms, but is not an inhibitor of one, two or all ofsuch Akt isoforms that have been modified to delete the PH domain, thehinge region or both the PH domain and the hinge region.

The present invention is further directed to a method of inhibiting Aktactivity which comprises administering to a mammal in need thereof apharmaceutically effective amount of the instant compound.

The compounds of this invention may be administered to mammals,including humans, either alone or, in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate buryrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of sterile injectableaqueous solutions. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of Formula A may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula A are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a composition according to this invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

The dosage regimen utilizing the compounds of the instant invention canbe selected in accordance with a variety of factors including type,species, age, weight, sex and the type of cancer being treated; theseverity (i.e., stage) of the cancer to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to treat, for example, to prevent,inhibit (fully or partially) or arrest the progress of the disease. Forexample, compounds of the instant invention can be administered in atotal daily dose of up to 10,000 mg. Compounds of the instant inventioncan be administered once daily (QD), or divided into multiple dailydoses such as twice daily (BID), and three times daily (TID). Compoundsof the instant invention can be administered at a total daily dosage ofup to 10,000 mg, e.g., 2,000 mg, 3,000 mg, 4,000 mg, 6,000 mg, 8,000 mgor 10,000 mg, which can be administered in one daily dose or can bedivided into multiple daily doses as described above.

For example, compounds of the instant invention can be administered in atotal daily dose of up to 1,000 mg. Compounds of the instant inventioncan be administered once daily (QD), or divided into multiple dailydoses such as twice daily (BID), and three times daily (TID). Compoundsof the instant invention can be administered at a total daily dosage ofup to 1,000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1,000mg, which can be administered in one daily dose or can be divided intomultiple daily doses as described above.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of a compound of theinstant invention may be administration one to six days per week or itmay mean administration in cycles (e.g. daily administration for two toeight consecutive weeks, then a rest period with no administration forup to one week) or it may mean administration on alternate days.

In addition, the compounds of the instant invention may be administeredaccording to any of the schedules described above, consecutively for afew weeks, followed by a rest period. For example, the compounds of theinstant invention may be administered according to any one of theschedules described above from two to eight weeks, followed by a restperiod of one week, or twice daily at a dose of 100-500 mg for three tofive days a week. In another particular embodiment, the compounds of theinstant invention may be administered three times daily for twoconsecutive weeks, followed by one week of rest.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter referred to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention. In addition,anti-cancer treatment can be administered during the period ofadministration of a compound of the instant invention but does not needto occur over the entire treatment period of a compound of the instantinvention.

The instant compounds are also useful in combination with therapeutic,chemotherapeutic and anti-cancer agents. Combinations of the presentlydisclosed compounds with therapeutic, chemotherapeutic and anti-canceragents are within the scope of the invention. Examples of such agentscan be found in Cancer Principles and Practice of Oncology by V. T.Devita and S. Hellman (editors), 6^(th) edition (Feb. 15, 2001),Lippincott Williams & Wilkins Publishers. A person of ordinary skill inthe art would be able to discern which combinations of agents would beuseful based on the particular characteristics of the drugs and thecancer involved. Such agents include the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic/cytostatic agents, antiproliferative agents, prenyl-proteintransferase inhibitors, HMG-CoA reductase inhibitors and otherangiogenesis inhibitors, HIV protease inhibitors, reverse transcriptaseinhibitors, inhibitors of cell proliferation and survival signaling,bisphosphonates, aromatase inhibitors, siRNA therapeutics, γ-secretaseinhibitors, agents that interfere with receptor tyrosine kinases (RTKs)and agents that interfere with cell cycle checkpoints. The instantcompounds are particularly useful when co-administered with radiationtherapy.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators includefininasteride and other 5α-reductase inhibitors, nilutamide, flutamide,bicalutamide, liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, 1LX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell myosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, histone deacetylase inhibitors,inhibitors of kinases involved in mitotic progression, inhibitors ofkinases involved in growth factor and cytokine signal transductionpathways, antimetabolites, biological response modifiers,hormonal/anti-hormonal therapeutic agents, haematopoietic growthfactors, monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, andaurora kinase inhibitors.

Examples of cytotoxic/cytostatic agents include, but are not limited to,sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin,altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine,nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine,improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride,pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, anrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin,galarubicin, elinafide,MEN10755,4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin(see WO 00/50032), Raf kinase inhibitors (such as Bay43-9006) and mTORinhibitors (such as Wyeth's CCI-779).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteosome inhibitors include but are not limited tolactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797. In an embodiment the epothilones are notincluded in the microtubule inhibitors/microtubule-stabilising agents.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine, (5a, 5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydro-oxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in Publications WO03/039460,WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678,WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417,WO04/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638,WO5/019206, WO05/019205, WO05/018547, WO05/017190, US2005/0176776. In anembodiment inhibitors of mitotic kinesins include, but are not limitedto inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E,inhibitors of MCAK and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Furtherreference to other histone deacetylase inhibitors may be found in thefollowing manuscript; Miller, T. A. et al. J. Med. Chem.46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,1′-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine,3-aminopyridine-2-carboxaldehyde thiosemicarbazone and trastuzumab.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) andcerivastatin (also known as rivastatin and BAYCHOL®; see U.S. Pat. No.5,177,080). The structural formulas of these and additional HMG-CoAreductase inhibitors that may be used in the instant methods aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol.,Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol.93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol.Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in U.S. Ser. Nos.60/310,927 (filed Aug. 8, 2001) and 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the CHK11 and CHK12 kinasesand cdk and cde kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refer tocompounds that inhibit RTKs and therefore mechanisms involved inoncogenesis and tumor progression. Such agents include inhibitors ofc-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors ofRTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

“Inhibitors of cell proliferation and survival signalling pathway” referto compounds that inhibit signal transduction cascades downstream ofcell surface receptors. Such agents include inhibitors ofserine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in WO 02/083064, WO 02/083139, WO 02/083140, US2004-0116432, WO 02/083138, US 2004-0102360, WO 03/086404, WO 03/086279,WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130, WO2005/100356, WO 2005/100344, US 2005/029941, US 2005/44294, US2005/43361, 60/734,188, 60/652,737, 60/670,469), inhibitors of Rafkinase (for example BAY-43-9006), inhibitors of MEK (for example CI-1040and PD-098059), inhibitors of mTOR (for example Wyeth CCI-779), andinhibitors of PI3K (for example LY294002).

As described above, the combinations with NSAID's are directed to theuse of NSAID's which are potent COX-2 inhibiting agents. For purposes ofthis specification an NSAID is potent if it possesses an IC₅₀ for theinhibition of COX-2 of 1 μM or less as measured by cell or microsomalassays.

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. No. 5,474,995, U.S. Pat. No.5,861,419, U.S. Pat. No. 6,001,843, U.S. Pat. No. 6,020,343, U.S. Pat.No. 5,409,944, U.S. Pat. No. 5,436,265, U.S. Pat. No. 5,536,752, U.S.Pat. No. 5,550,142, U.S. Pat. No. 5,604,260, U.S. Pat. No. 5,698,584,U.S. Pat. No. 5,710,140, WO 94/15932, U.S. Pat. No. 5,344,991, U.S. Pat.No. 5,134,142, U.S. Pat. No. 5,380,738, U.S. Pat. No. 5,393,790, U.S.Pat. No. 5,466,823, U.S. Pat. No. 5,633,272 and U.S. Pat. No. 5,932,598,all of which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;and5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; ora pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to, the following: parecoxib, BEXTRA® and CELEBREX® or apharmaceutically acceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase,IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the αvβ5 integrin, tocompounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₃₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples oftyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, STI571, CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571 A,N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-8 (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malingnancies. PPAR-γ and PPAR-β are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999; 274:9116-9121; Invest. Ophthalmol. Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998; 5(8):1105-13), andinterferon gamma (J. Immunol. 2000; 164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In another embodiment, conjunctive therapywith an anti-emesis agent selected from a neurokinin-1 receptorantagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosedfor the treatment or prevention of emesis that may result uponadministration of the instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications, which are incorporatedherein by reference.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with P450 inhibitors including:xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine,methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin,cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine,dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem,terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodoneand nelfinavir.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with Pgp and/or BCRP inhibitorsincluding: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorginC, Ko 132, Ko134, Iressa, Imatnib mesylate, EKI-785, C11033, novobiocin,diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A,flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine,verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone,XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979,OC144-093, erythromycin, vincristine, digoxin and talinolol.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be useful for treating orpreventing breast cancer in combination with aromatase inhibitors.Examples of aromatase inhibitors include but are not limited to:anastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

The compounds of the instant invention may also be administered incombination with γ-secretase inhibitors and/or inhibitors of NOTCHsignaling. Such inhibitors include compounds described in WO 01/90084,WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370,WO 2005/030731, WO 2005/014553, U.S. Ser. No. 10/957,251, WO2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137,WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO02/47671 (including LY-450139).

Inhibitors of Akt, as disclosed in the following publications; WO02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US2005/029941, US 2005/44294, US 2005/43361, 60/734,188, 60/652,737,60/670,469, and including compounds of the instant invention, are alsouseful in combination with potassium salts, magnesium salts,beta-blockers (such as atenolol) and endothelin-a (ETa)antagonists withthe goal of maintaining cardiovascular homeostasis.

Inhibitors of Akt, as disclosed in the following publications; WO02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US2004-0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US2005/029941, US 2005/44294, US 2005/43361, 60/734,188, 60/652,737,60/670,469, and including compounds of the instant invention, are alsouseful in combination with insulin, insulin secretagogues, PPAR-gammaagonists, metformin, somatostatin receptor agonists such as octreotide,DPP4 inhibitors, sulfonylureas and alpha-glucosidase inhibitors with thegoal of maintaining glucose homeostasis.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with PARP inhibitors.

A compound of the instant invention may also be useful for treatingcancer in combination with the following therapeutic agents: abarelix(Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®);Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol(Zyloprim®); altretamine (Hexylen®); amifostine (Ethyol®); anastrozole(Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®);azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules(Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®);bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral(Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®);carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine(Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®);celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®);cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine(Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide(Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine(Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®);daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin(Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukindiftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®);doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®);doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®);dromostanolone propionate (Dromostanolone®); dromostanolone propionate(Masterone Injection®); Elliott's B Solution (Elliott's B Solution®);epirubicin (Ellence®); Epoetin alfa (Epogen®); erlotinib (Tarceva®);estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide,VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®);floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®);fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin Implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide(Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®,Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®);lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®);megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®);mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (MesnexTabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C(Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®);nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®);Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®);paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-boundparticles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®);pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®);Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin(Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®);porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine(Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim(Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin(Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen(Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®);testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab(Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab(Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (UracilMustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®);vincristine (Oncovin®); vinorelbine (Navelbine®); zoledronate (Zometa®)and vorinostat (Zolinza®).

The compounds of the instant invention are useful for treating cancer incombination with taxanes.

The compounds of the instant invention are useful for treating cancer incombination with docetaxel (Taxotere®).

The compounds of the instant invention are useful for treating cancer incombination with vorinostat (Zolinza®).

The compounds of the instant invention are useful for treating cancer incombination with the aurora kinase inhibitor, MK-0457.

The compounds of the instant invention are useful for treating cancer incombination with the mTor inhibitor, AP 23573.

The compounds of the instant invention are useful for treating cancer incombination with the IGF1R inhibitor, MK-0646.

The compounds of the instant invention are useful for treating cancer incombination with satraplatin.

The compounds of the instant invention are useful for treating cancer incombination with lapatinib (Tykerb®).

Thus, the scope of the instant invention encompasses the use of theinstantly claimed compounds in combination with a second compoundselected from: an estrogen receptor modulator, an androgen receptormodulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent,an antiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, PPAR-γ agonists,PPAR-8 agonists, an inhibitor of inherent multidrug resistance, ananti-emetic agent, an agent useful in the treatment of anemia, an agentuseful in the treatment of neutropenia, an immunologic-enhancing drug,an inhibitor of cell proliferation and survival signaling, abisphosphonate, an aromatase inhibitor, an siRNA therapeutic,γ-secretase inhibitors, agents that interfere with receptor tyrosinekinases (RTKs), an agent that interferes with a cell cycle checkpointand any of the therapeutic agents listed above.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

In an embodiment, the angiogenesis inhibitor to be used as the secondcompound is selected from a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, or an antibody to VEGF. In an embodiment, the estrogenreceptor modulator is tamoxifen or raloxifene.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of the instant invention in combination with radiation therapyand/or in combination with a second compound selected from: an estrogenreceptor modulator, an androgen receptor modulator, a retinoid receptormodulator, a cytotoxiccytostatic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor, anangiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an inhibitorof inherent multidrug resistance, an anti-emetic agent, an agent usefulin the treatment of anemia, an agent useful in the treatment ofneutropenia, an immunologic-enhancing drug, an inhibitor of cellproliferation and survival signaling, a bisphosphonate, an aromataseinhibitor, an siRNA therapeutic, γ-secretase inhibitors, agents thatinterfere with receptor tyrosine kinases (RTKs), an agent thatinterferes with a cell cycle checkpoint and any of the therapeuticagents listed above.

And yet another embodiment of the invention is a method of treatingcancer that comprises administering a therapeutically effective amountof a compound of the instant invention in combination with paclitaxel ortrastuzumab.

The invention further encompasses a method of treating or preventingcancer that comprises administering a therapeutically effective amountof a compound of the instant invention in combination with a COX-2inhibitor.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of the instant invention and a secondcompound selected from: an estrogen receptor modulator, an androgenreceptor modulator, a retinoid receptor modulator, acytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-proteintransferase inhibitor, an HMG-CoA reductase inhibitor, an HIV proteaseinhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor,a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of cell proliferationand survival signaling, a bisphosphonate, an aromatase inhibitor, ansiRNA therapeutic, γ-secretase inhibitors, agents that interfere withreceptor tyrosine kinases (RTKs), an agent that interferes with a cellcycle checkpoint and any of the therapeutic agents listed above.

All patents, publications and pending patent applications identified arehereby incorporated by reference.

Abbreviations used in the description of the chemistry and in theExamples that follow are: HPLC (high performance liquid chromatography)and TFA (trifluoroacetic acid).

The compounds of this invention may be prepared by employing reactionsas shown in the following Reaction Schemes, in addition to otherstandard manipulations that are known in the literature or exemplifiedin the experimental procedures. The illustrative Reaction Schemes below,therefore, are not limited by the compounds listed or by any particularsubstituents employed for illustrative purposes. Substituent numberingas shown in the Reaction Schemes does not necessarily correlate to thatused in the claims and often, for clarity, a single substituent is shownattached to the compound where multiple substituents are allowed underthe definitions of Formula A hereinabove.

Compound (I) in Reaction Schemes I can be prepared by the Suzukicoupling reaction between the heterocyclic chloride and thecorresponding benzylamine boronic ester (IV).

Compound (XV) in Reaction Schemes II can be prepared via the generalsynthetic methods and procedures found in WO2009/021992. The requisitestarting material (XVI) can be prepared according to Scheme I. Keyintermediates are in some cases commercially available or can beprepared according to literature procedures.

Compound (XVIII) in Reaction Schemes III can be prepared via the generalsynthetic methods and procedures found in WO2009/021992. The requisiteintermediates are in some cases commercially available or can beprepared according to literature procedures.

EXAMPLES

Examples and schemes provided are intended to assist in a furtherunderstanding of the invention. Particular materials employed, speciesand conditions are intended to be further illustrative of the inventionand do not limit the reasonable scope thereof.

Example A-1

1-[4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine (A-1)

To a mixture of 1-B (6 g, for preparation see WO2009/021992) andtert-butyl{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate1-A (6 g, for preparation see WO2008/070016) in 210 ml of1,2-dimethoxyethane;dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.96 g) and 42 ml of a 10% w/w sodium carbonatesolution is added. The resulting mixture is heated to 80° C. under aninert gas atmosphere for 15 h. The work up is performed by diluting thereaction mixture with water and dichloromethane, separating the phasesand extraction of the aqueous phase with dichloromethane. The combinedorganic layers are dried over sodium sulphate and evaporated. Theresidue is suspended in ethyl acetate and the resulting mixture stirredfor 2 h at room temperature. The product is collected by filtration andtreated with 30 mL TFA in 30 mL dichloromethane for 1 hr. The resultingmixture is concentrated and purified via reverse phase HPLC to affordthe desired product.

Example B-1

1-[4-(2-isopropyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine(B-1)

To a mixture of 2-B (6 g, for preparation see WO2009/021992) andtert-butyl{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate1-A (6 g, for preparation see WO2008/070016) in 210 ml of1,2-dimethoxyethane;dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.96 g) and 42 ml of a 10% w/w sodium carbonatesolution is added. The resulting mixture is heated to 80° C. under aninert gas atmosphere for 15 h. The work up is performed by diluting thereaction mixture with water and dichloromethane, separating the phasesand extraction of the aqueous phase with dichloromethane. The combinedorganic layers are dried over sodium sulphate and evaporated. Theresidue is suspended in ethyl acetate and the resulting mixture stirredfor 2 h at room temperature. The product is collected by filtration andtreated with 30 mL TFA in 30 mL dichloromethane for 1 hr. The resultingmixture is concentrated and purified via reverse phase HPLC to affordthe desired product.

Example C-1

1-[4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine(C-1)

To a mixture of 3-B (6 g, for preparation see WO2009/021992) andtert-butyl{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamate1-A (6 g, for preparation see WO2008/070016) in 210 ml of1,2-dimethoxyethane;dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.96 g) and 42 ml of a 10% w/w sodium carbonatesolution is added. The resulting mixture is heated to 80° C. under aninert gas atmosphere for 15 h. The work up is performed by diluting thereaction mixture with water and dichloromethane, separating the phasesand extraction of the aqueous phase with dichloromethane. The combinedorganic layers are dried over sodium sulphate and evaporated. Theresidue is suspended in ethyl acetate and the resulting mixture stirredfor 2 h at room temperature. The product is collected by filtration andtreated with 30 mL TFA in 30 mL dichloromethane for 1 hr. The resultingmixture is concentrated and purified via reverse phase HPLC to affordthe desired product.

Compounds disclosed in Table 1 are prepared according to proceduresdescribed herein and in WO2009/021992 using appropriate startingmaterials.

TABLE 1 Example Structure Name Molecular Weight D

1-[4-(3,6- diphenylimidazo[1,2- a]pyrimidin-7- yl)phenyl]cyclobutanamine416.20 E

3-amino-3-[4-(3,6- diphenylimidazo[1,2- a]pyrimidin-7-yl)phenyl]-1-methylcyclobutanol 446.21 F

3-amino-1-methyl-3-[4-(2- methyl-3,6- diphenylimidazo[1,2-a]pyrimidin-7- yl)phenyl]cyclobutanol 460.23 G

1-[4-(2-methyl-3,6- diphenylimidazo[1,2- a]pyrimidin-7-yl)phenyl]cyclobutanamine 430.22 H

3-amino-1-methyl-3-[4-(2- methyl-6- phenylpyrazolo[1,5- a]pyrimidin-5-yl)phenyl]cyclobutanol 384.20 I

3-amino-1-methyl-3-[4-(6- phenylpyrazolo[1,5- a]pyrimidin-5-yl)phenyl]cyclobutanol 370.18 J

1-[4-(6- phenylpyrazolo[1,5- a]pyrimidin-5- yl)phenyl]cyclobutanamine340.17 K

1-[4-(2-methyl-6- phenyl[1,2,4]triazolo[1,5- a]pyrimidin-5-yl)phenyl]cyclobutanamine 355.18 L

3-amino-1-methyl-3-[4-(2- methyl-6- phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5- yl)phenyl]cyclobutanol 385.19 M

1-[4-(3,6- diphenylimidazo[1,2- a]pyrimidin-7- yl)phenyl]methanamine376.17 N

1-[4-(6- phenylpyrazolo[1,5- a]pyrimidin-5- yl)phenyl]methanamine 300.14O

1-[4-(2-methyl-6- phenyl[1,2,4]triazolo[1,5- a]pyrimidin-5-yl)phenyl]methanamine 315.15

OTHER EXAMPLES

Examples and schemes provided are intended to assist in a furtherunderstanding of the invention. Particular materials employed, speciesand conditions are intended to be further illustrative of the inventionand do not limit the reasonable scope thereof.

{1-[4-(3-Dimethylamino-2-phenyl-acryloyl)-phenyl]-cyclobutyl}-carbamicAcid tert-butyl Ester (1)

Step A: [1-(4-Cyano-phenyl)-cyclobutyl]-carbamic Acid Tert-butyl Ester(1-2)

A mixture of [1-(4-Chloro-phenyl)-cyclobutyl]-carbamic acid tert-butylester 1-1 (prepared according to WO2008/070016; 1.57 g, 5.6 mmol),Zn(CN)₂ (395 mg, 3.37 mmol), Pd₂(dba)₃ (257 mg, 0.28 mmol), dppf (311mg, 0.56 mmol), Zinc powder (219 mg, 3.37 mmol) and 20 mL of DMF washeated to 100.deg.C for 2 hrs under nitrogen atmosphere. After coolingto room temperature, the mixture was poured into water and extractedwith EA for three times. The combined EA layer was washed with water,brine and concentrated to give a residue, which was purified by silicagel chromatography eluting with EA/PE (3/1) to give 1.23 g of compound1-2. MS (ESI) m/e (M+H⁺): observed=273.2, calculated=273.2.

Step B: [1-(4-Phenylacetyl-phenyl)-cyclobutyl]-carbamic Acid Tert-butylEster (1-3)

A solution of i-PrMgCl (9.65 mL, 19.3 mmol) in THF was added dropwise toa solution of compound 1-2 (5.24 g, 19.3 mmol) in dry THF at −5.deg.C.After stirring for 20 min, a solution of BnMgCl (29 mL, 2M, 58 mmol) inTHF was added dropwise to the reaction mixture. After completion ofaddition, the reaction mixture was stirred for 1 h at 0.deg.C, thenwarmed slowly to room temperature, and stirred for another 1 h. Thereaction was quenched with saturated NH₄ Cl solution, extracted withethyl acetate. Separated and collected the organic layer, and theaqueous solution was washed EA for two times. The combined organic layerwas washed with brine, dried and concentrated in vacuo to get the crudeproduct, which was purified by silica chromatography to give 5.5 g ofketone 1-3. MS (ESI) m/e (M+H⁺): observed=388.2 (+23)/332.2 (−56)calculated=388.2 (+23)/332.2 (−56)

Step C:{1-[4-(3-Dimethylamino-2-phenyl-acryloyl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (1)

To a solution of compound 1-3 (5.0 g, 13.7 mmol) in toluene (30 mL) wasadded DMFDMA (18.15 g, 68.4 mmol) and the mixture was heated at refluxfor 4 hours. The TLC showed the starting material was disappeared. Themixture was cooled and the formed white solid was collected. Afterwashed by PE, the solid was dried in vacuum to get the product 1.

MS (ESI) m/e (M+H⁺): observed=421.3; calculated=421.2

{1-[4-(3-Dimethylamino-2-phenyl-acryloyl)-phenyl]-3-hydroxy-3-methyl-cyclobutyl}-carbamicAcid Tert-butyl Ester (2)

Step A: [1-(4-Cyano-phenyl)-3-hydroxy-3-methyl-cyclobutyl]-carbamic AcidTert-Butyl Ester (2-2)

A mixture of [1-(4-Bromo-phenyl)-3-hydroxy-3-methyl-cyclobutyl]-carbamicacid tert-butyl ester 2-1 (prepared according to WO2008/070041; 3.56 g,10 mmol), Zn (1 g, 15 mmol), Zn(CN)₂ (1.76 g, 15 mmol), Pd2(dba)₃ (0.5g, 0.5 mmol) and DPPF (300 mg, 0.5 mmol) in 30 mL of DMF was stirred at100° C. for 2 hrs under N2. After the mixture was cooled to rt, 100 mLof water was added and product was extracted with ethyl acetate 100mL×3. The organic layer was combined, washed with brine, dried oversodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel chromatography using EA/PE (1:2) as eluant to givecompound 2-2.

MS (ESI) m/e (M+H⁺): observed=303.3, calculated=303.2.

Step B:[3-Hydroxy-3-methyl-1-(4-phenylacetyl-phenyl)-cyclobutyl]-carbamic AcidTert-butyl Ester (2-3)

A solution of i-PrMgCl (9.65 mL, 19.3 mmol) in THF was added dropwise toa solution of compound 2-2 (5.84 g, 19.3 mmol) in dry THF at −5.deg.C.After stirring for 20 min, a solution of BnMgCl (58 mL, 2M, 116 mmol) inTHF was added dropwise to the reaction mixture. After completion ofaddition, the reaction mixture was stirred for 1 h at 0.deg.C, thenwarmed slowly to room temperature, and stirred for another 1 h. Thereaction was quenched with saturated NH₄ Cl solution, extracted withethyl acetate. Separated and collected the organic layer, and theaqueous solution was washed EA for two times. The combined organic layerwas washed with brine, dried and concentrated in vacuo to get the crudeproduct, which was purified by silica chromatography to afford 6.2 g ofketone 2-3.

MS (ESI) m/e (M+H⁺): observed=418.2 (+23)/340.2 (−56) calculated=418.2(+23)/340.2 (−56)

Step C:{1-[4-(3-Dimethylamino-2-phenyl-acryloyl)-phenyl]-3-hydroxy-3-methyl-cyclobutyl}-carbamicAcid Tert-butyl Ester (2)

To a solution of compound 2-3 (3.96 g, 10 mmol) in toluene (20 mL) wasadded DMFDMA (9.2 g, 35 mmol) and the mixture was heated at reflux for 4hours. The mixture was cooled and the formed white solid was collected.After washed by PE, the solid was dried in vacuum to get the product 2.

MS (ESI) m/e (M+H⁺): observed=451.3; calculated=451.2

Example (3-6)

Step A: 6-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-5,7-diol (3-2)

A mixture of 1H-[1,2,4]Triazol-3-ylamine SM (500 mg, 5.95 mmol) and2-Phenyl-malonic acid diethyl ester 3-1 (1.41 g, 5.95 mmol) inN,N-dibutylbutan-1-amine (5 mL) was stirred at 185° C. overnight. Themixture was partitioned with two layers after cooling to roomtemperature. The top layer was removed and the lower layer was washedwith cold PE. The resulting solution was concentrated and extracted witha mixture of diethyl ether and 10% w/w NaOH solution. The organic layerwas discarded and aqueous layer acidified with concentrated HCl. Theprecipitated product was collected by filtration to afford compound 3-2.MS (ESI) m/e (M+11) 229.1

Step B: 5,7-Dichloro-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (3-3)

Compound 3-2 (600 mg, 2.6 mmol) was suspended in 3 mL of POCl₃ and themixture was stirred at 100° C. for 6 h. The solvent was removed and theresidue was dissolved in a mixture of dichloromethane and ice water. Theorganic phase was separated and aqueous phase was extracted withdichloromethane twice. The combined organic phase was dried over Na₂SO₄and evaporated to yield the crude product 3-3, which was used withoutfurther purification.

MS (ESI) m/e (M+H⁺) 266.1

Step C: 5-Chloro-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (3-4)

To the solution of 3-3 (100 mg, 0.37 mmol) in a co-solvent of AcOH (0.2mL), MeOH (0.2 mL) and THF (1.2 mL) was added Zn/Cu pair (73 mg, 0.6mmol) and the mixture was stirred at r.t. for 3 h. The mixture wasfiltered to remove the insoluble solid and the filtrate was diluted with15 mL of DCM, the combined organic phase was washed with 0.1N HCl aq.and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by prep.TLC to give 43 mg of 3-4.

MS (ESI) m/e (M+H⁺) 231.4

Step D:[4-(6-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-benzyl]-carbamic AcidTert-butyl Ester (3-5)

A mixture of compound 3-4 (60 mg 0.24 mmol),[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acidtert-butyl ester (100 mg, 0.3 mmol), aq.Na₂ CO₃ (2M, 0.70 mmol, 0.35 mL)and Pd(DPPF)Cl₂ (10 mg) in dioxane (3 mL) was heated at 100° C. inmicrowave system under N₂ atmosphere for 30 min. After cooling, themixture was diluted with 15 mL of DCM, the combined organic phase waswashed with 0.1N HClaq and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by prep.TLC to give 46 mg of 3-5.MS (ESI) m/e (M+H) 402.1

Step E: 4-(6-Phenyl-[1,2,4-triazolo[1,5-a]pyrimidin-5-yl]-benzylamine(3-6)

To the solution of 3-5 (46 mg, 0.11 mmol) in 1 mL of DCM was added TFA(1 mL) and the mixture was stirred at room temperature for 3 h. Themixture was concentrated by evaporation and the residue was purified byprep.HPLC to give the product 3-6.

MS (ESI) m/e (M+H⁺) 302.1

¹H NMR (400 MHz, MeOH): δ 8.50 (s, 1H), 7.61-7.50 (m, 3H), 7.42-7.33 (m,5H), 7.28-7.22 (m, 2H), 4.13 (s, 2H)

The following compounds 3-7 to 3-8 were prepared in a similar manner toExample 3-6 using the appropriate materials commercially available.

LC/MS (ESI) observed Ex. Structure MW Compound Name [M + 1]+ 3-7

396.5 3-Amino-1-cyclopropyl-3-[4- (6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]- cyclobutanol 397.4 3-8

300.4 4-(6-Phenyl-pyrazolo[1,5- a]pyrimidin-5-yl)- benzylamine 301.1

Example (4-2)

{1-[4-(6-Phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (4-1)

Compound 1 (1.2 g, 2.9 mmol) and 2-aminoimidazole (0.77 g 4.3 mmol) wereadded into a solution of AcOH (2 mL) and EtOH (10 mL). The mixture washeated to reflux and stirred overnight. The solution was cooled to r.t.and diluted with 30 mL of DCM. The organic phase was washed with 0.1NHCl(aq) and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography to give 1.2 gof 4-1 as a yellow solid. MS (ESI) m/e (M+H⁺): 441.3

1-[4-(6-Phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutlamine(4-2)

To a solution of 4-1 (45 mg, 0.1 mmol) in 1 mL of MeOH was added 4MHCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h.The mixture was concentrated by evaporation and the residue was purifiedby prep.HPLC to give the product 4-2.

MS (EST) m/e (M+H⁺): 341.3

¹H NMR (400 MHz, MeOH): δ 8.59 (s, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.64 (d,J=8.0 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.40 (d, J=1.2 Hz, 1H), 2.65-2.52(m, 2H), 2.48-2.39 (m, 2H), 2.18-2.08 (m, 2H), 1.86-1.73 (m, 2H)

Example (4-4)

{1-[4-(3-Bromo-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (4-3)

To a solution of compound 4-1 (100 mg, 0.227 mmol) in CHCl₃ (5 mL) wasadded NBS (40 mg 0.227 mmol.) and the mixture was heated to reflux for 2hrs. After cooling, the mixture was diluted with 15 mL of DCM, thecombined organic phase was washed with 0.1N HCl(aq) and brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified byprep.TLC to give 150 mg of 4-3.

MS (ESI) m/e (M+1) 520.3

1-[4-(3-Bromo-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine(4-4)

To a solution of 4-3 (52 mg, 0.1 mmol) in 1 mL of MeOH was added 4MHCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h.The mixture was concentrated by evaporation and the residue was purifiedby prep.HPLC to give the product 4-4. MS (ESI) m/e (M+H⁺): 420.3

¹H NMR (400 MHz, MeOH): δ 8.98 (s, 1H), 7.60 (brs, 4H), 7.28 (brs, 6H),5.65 (d, J=17.2 Hz, 1H), 5.49-7.42 (m, 1H), 5.07 (d, J=10.8 Hz, 1H),2.81-2.72 (m, 2H), 2.69-2.56 (m, 2H), 2.30-2.22 (m, 2H), 1.96-1.89 (m,2H).

Example (4-6)

{1-[4-(6-Phenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (4-5)

A mixture of compound 4-3 (100 mg 0.193 mmol), Tributyl-vinyl-stannane(92 mg, 0.58 mmol), K₂ CO₃ (27 mg, 0.193 mmol), Et₄NCl (31.8 mg 0.193mmol) and Pd(PPh₃)₂Cl₂ (10 mg) in THF (5 mL) was heated at 100° C. inmicrowave system under N2 atmosphere for 45 min. After cooling, themixture was diluted with 15 mL of DCM, the combined organic phase waswashed with 0.1N HClaq and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by prep.TLC to give 78 mg of 4-5.

MS (ESI) m/e (M+Hf): 467.3

1-[4-(6-Phenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine(4-6)

To the solution of 4-5 (47 mg, 0.1 mmol) in 1 mL of MeOH was added 4MHCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h.The mixture was concentrated by evaporation and the residue was purifiedby prep.HPLC to give the product 4-6.

MS (ESI) m/e (M+H): 367.3

¹H NMR (400 MHz, MeOD): δ 9.02 (s, 1H), 8.08 (s, 1H), 7.34 (d, J=1.6 Hz,1H), 7.32-7.25 (m, 4H), 7.24-7.20 (m, 5H), 6.95 (dd, J=16.4 Hz, 8.4 Hz,2H), 6.51 (d, J=8.4 Hz, 1H), 3.50 (s, 3H), 2.62-2.55 (m, 2H), 2.53-2.49(m, 2H), 2.25-2.18 (m, 1H), 1.96-1.89 (m, 1H).

Example (4-8)

(1-{4-[3-(2-Methoxy-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutyl)-carbamicAcid Tert-butyl Ester (4-7)

A mixture of compound 4-3 (52 mg 0.1 mmol), 2-methoxy]phenyl boronicacid (30 mg, 0.15 mmol), aq.Na₂ CO₃ (2M, 0.25 mmol, 0.12 mL) andPd(DPPF)Cl₂ (10 mg) in dioxane (3 mL) was heated at 100° C. in microwavesystem under N₂ atmosphere for 30 min. After cooling, the mixture wasdiluted with 15 mL of DCM, the combined organic phase was washed with0.1N HCl aq and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep.TLC to give 36 mg of 4-7.

MS (ESI) m/e (M+H): 547.5

1-{4-[3-(2-Methoxy-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine(4-8)

To a solution of 4-7 (55 mg, 0.1 mmol) in 1 mL of MeOH was added 4MHCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h.The mixture was concentrated by evaporation and the residue was purifiedby prep.HPLC to give the product 4-8.

MS (ESI) m/e (M+H^(f)): 447.5

¹NMR (400 MHz, MeOD): δ 9.02 (s, 1H), 8.08 (s, 1H), 7.34 (d, J=1.6 Hz,1H), 7.32-7.25 (m, 4H), 7.24-7.20 (m, 5H), 6.95 (dd, J=16.4 Hz, 8.4 Hz,2H), 6.51 (d, J=8.4 Hz, 1H), 3.50 (s, 3H), 2.62-2.55 (m, 2H), 2.53-2.49(m, 2H), 2.25-2.18 (m, 1H), 1.96-1.89 (m, 1H).

Example (4-10)

{-[4-(3-Cyano-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (4-9)

A mixture of compound 4-3 (80 mg 0.154 mmol.), Zn(CN)₂ (11 mg, 0.0906mmol.), Zn (1 mg 0.015 mmol.) and Pd(dppf)Cl₂ (10 mg) in DMA (2 mL) washeated at 160° C. in microwave system for 45 min. After cooling, themixture was diluted with 15 mL of DCM, the combined organic phase waswashed with 0.1N HCl(aq) and brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by prep.TLC to give 60 mg of 4-9.

MS (ESI) m/e (M+H⁺): 466.1

7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carbonitrile(4-10)

To a solution of 4-9 (46 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 4-10.

MS (ESI) m/e (M+H⁺): 366.1

¹H NMR (400 MHz, MeOD): δ 8.86 (s, 1H), 8.46 (s, 1H), 7.62 (dd, J=12.0Hz, 8.4 Hz, 4H), 7.29-7.26 (m, 5H), 2.80-2.70 (m, 2H), 2.67-2.56 (m,2H), 2.29-2.13 (m, 1H), 2.06-1.90 (m, 1H)

Example (4-11)

7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carboxylicAcid Amide (4-11)

To a suspension of compound 4-10 (40 mg 0.11 mmol.) and K₂ CO₃ (30 mg,0.22 mmol) in DMSO (1.0 mL) was added 0.1 mL of H₂O₂(30% aq.) and themixture was heated at 60° C. for 3 h. After cooling, the mixture wasdiluted with 20 mL of EA, the combined organic phase was washed withsat.NaHSO₃ (aq) and brine, dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by prep.HPLC to give 19 mg of 4-11.

MS (ESI) m/e (M+H⁺): 384.3

¹H NMR (400 MHz, MeOD): δ 8.87 (s, 1H), 8.12 (s, 1H), 7.68 (dd, J=7.6Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.33-7.25 (m, 5H), 2.81-2.74 (m, 2H),2.66-2.59 (m, 2H), 2.29-2.24 (m, 1H), 1.98-1.92 (m, 1H).

The following compound 4-14 was prepared similarly to Example 4-4; 4-15was prepared similarly to Example 4-8; 4-16 was prepared similarly toExample 4-6.

LC/MS (ESI) found Ex. Structure MW Compound Name [M + 1]+ 4-14

374.9 1-[4-(3-Chloro-6-phenyl- imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine 375.7 4-15

354.5 1-[4-(3-Methyl-6-phenyl- imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine 355.2 4-16

406.5 1-{4-[3-(2-Cyclopropyl-vinyl)- 6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}- cyclobutylamine 407.1

Example (5-3)

{1-[4-(2-Amino-5-phenyl-pyrimidin-4-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (5-1)

To a solution of compound 1 (3 g, 7.2 mmol) and guanidine (2 g, 35 mmol)in DMF (15 mL) was added MeONa (1.8 g, 35 mmol) and the mixture washeated to 100° C. and stirred for 4 h. The solution was cooled to r.t.and diluted with 80 mL of EA. The organic phase was washed with 0.1NHClaq and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography to give 2.1 gof 5-1 as a yellow solid.

MS (ESI) m/e (M+H⁺): 417.3

{1-[4-(2,6-Diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (5-2)

A mixture of 5-1 (150 mg, 0.36 mmol) and 2-Bromo-1-phenyl-ethanone (110mg, 0.54 mmol) in ethanol (2 mL) was heated to 100° C. and stirred for45 mins under microwave radiation. The mixture was cooled to r.t. anddiluted with 20 mL of DCM. The organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby prep.TLC to give 90 mg of 5-2.

MS (ESI) m/e (M+H⁺): 517.4

1-[4-(2,6-Diphenyl-imidazol[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine(5-3)

To the solution of 5-2 (52 mg, 0.1 mmol) in 1 mL of MeOH was added 4MHCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h.The mixture was concentrated by evaporation and the residue was purifiedby prep.HPLC to give the product 5-3.

MS (ESI) m/e (M+H⁺): 417.4

¹H NMR (400 MHz, MeOD): δ 9.11 (s, 1H), 8.45 (s, 1H), 8.00 (d, J=7.6 Hz,2H), 7.68 (d, J=8.4 Hz, 2H), 7.61-7.50 (m, 5H), 7.47-7.41 (m, 3H),7.41-7.35 (m, 2H), 3.33-3.32 (m, 2H), 3.32-2.74 (m, 2H), 2.28-2.25 (m,1H), 1.99-1.96 (m, 1H).

Example (5-5)

{1-[4-(3-Bromo-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (5-4)

To a solution of compound 5-2 (110 mg, 0.2 mmol) in CHCl₃ (5 mL) wasadded NBS (40 mg 0.22 mmol.) and the mixture was heated to reflux for 1hrs. After cooling, the mixture was diluted with 15 mL of DCM, thecombined organic phase was washed with 0.1N HClaq and brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by prep.TLCto give 71 mg of 5-4.

MS (ESI) m/e (M+H⁺) 596.3

1-[4-(3-Bromo-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine(5-5)

To the solution of 5-4 (59 mg, 0.1 mmol) in 1 mL of MeOH was added 4MHCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h.The mixture was concentrated by evaporation and the residue was purifiedby prep.HPLC to give the product 5-5.

MS (ESI) m/e (M+H⁺): 496.3

¹H NMR (400 MHz, MeOD): δ 8.26 (s, 1H), 7.80 (d, J=7.6 Hz, 2H), 7.68 (d,J=8.4 Hz, 2H), 7.61-7.50 (m, 5H), 7.47-7.41 (m, 3H), 7.41-7.35 (m, 2H),3.33-3.32 (m, 2H), 3.32-2.74 (m, 2H), 2.28-2.25 (m, 1H), 1.99-1.96 (m,1H).

Example (5-7)

(1-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutyl)-carbamicAcid Tert-butyl Ester (5-6)

A mixture of compound 5-4 (60 mg 0.1 mmol), 3,5-ditrifluoromethyl phenylboronic acid (38 mg, 0.15 mmol), aq.Na₂ CO₃ (2M, 0.25 mmol, 0.12 mL) andPd(DPPF)Cl₂ (10 mg) in dioxane (3 mL) was heated at 100° C. in microwavesystem under N₂ atmosphere for 30 min. After cooling, the mixture wasdiluted with 15 mL of DCM, the combined organic phase was washed with0.1N HClaq and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep.TLC to give 38 mg of 5-6.

MS (ESI) m/e (M+H⁺): 728.6

1-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine(5-7)

To the solution of 5-6 (38 mg, 0.05 mmol) in 1 mL of MeOH was added 4MHCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h.The mixture was concentrated by evaporation and the residue was purifiedby prep.HPLC to give the product 5-7.

MS (ESI) m/e (M+H⁺): 628.3

¹H NMR (400 MHz, MeOD): δ 8.57 (s, 1H), 8.24 (s, 2H), 8.16 (s, 1H), 7.67(d, J=8.4 Hz, 2H), 7.60 (m, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.44-7.7.30 (m,8H), 2.79 (m, 2H), 2.62 (m, 2H), 2.26 (m, 1H), 2.00 (m, 1H)

Example (5-9)

{1-[4-(2,6-Diphenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (5-8

A mixture of compound 5-4 (120 mg 0.2 mmol), Tributyl-vinyl-stannane (95mg, 0.6 mmol), K₂ CO₃ (30 mg, 0.2 mmol), Et₄ NCl (35 mg 0.2 mmol) andPd(PPh₃)₂Cl₂ (10 mg) in THF (3 mL) was heated at 10° C. in microwavesystem under N₂ atmosphere for 45 min. After cooling, the mixture wasdiluted with 15 mL of DCM, the combined organic phase was washed with0.1N HClaq and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep.TLC to give 57 mg of 5-8.

MS (ESI) m/e (M+H⁺): 543.5

1-[4-(2,6-Diphenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine(5-9)

To the solution of 5-8 (54 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 5-9.

MS (ESI) m/e (M+H⁺): 443.5

¹H NMR (400 MHz, MeOD): δ 8.94 (d, J=2.0 Hz, 1H), 7.74 (d, J=7.2 Hz,2H), 7.55 (d, J=8.0 Hz, 2H), 7.47 (d, J=7.6 Hz, 2H), 7.38 (d, J=8.4 Hz,2H), 7.30 (m, 5H), 6.95 (dd, J=18.0 Hz, 12.0 Hz, 1H), 5.84 (d, J=18.0Hz, 1H), 5.68 (d, J=12.0 Hz, 1H), 2.65 (m, 2H), 2.50 (m, 2H), 2.14 (m,1H),1.86 (m, 1H)

The following compounds 5-11 to 5-17 were prepared in a similar mannerto Example 5-3 using the appropriate commercially available materials;5-18 was prepared similarly to Example 5-5; compounds 5-19 to 5-22 wereprepared similarly to Example 5-7; 5-23 was prepared similarly toExample 5-9.

LC/MS (ESI) found Ex. Structure MW Compound Name [M + 1]+ 5-11

368.5 1-[4-(2-Ethyl-6-phenyl- imidazo[1,2-a]pyrimidin- 7-yl)-phenyl]-cyclobutylamine 369.3 5.12

408.4 1-[4-(6-Phenyl-2- trifluoromethyl- imidazo[1,2-a]pyrimidin-7-yl)-phenyl]- cyclobutylamine 409.2 5-13

412.5 7-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-imidazo[1,2-a]pyrimidine-2- carboxylic acid ethyl ester 413.3 5-14

384.4 7-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-imidazo[1,2-a]pyrimidine-2- carboxylic acid 385.2 5-15

398.5 7-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-imidazo[1,2-a]pyrimidine-2- carboxylic acid methyl ester 399.4 5-16

434.5 1-{4-[2-(4-Fluoro- phenyl)-6-phenyl- imidazo[1,2-a]pyrimidin-7-yl]-phenyl}- cyclobutylamine 435.2 5-17

430.6 1-[4-(6-Phenyl-2-p-tolyl- imidazo[1,2-a]pyrimidin- 7-yl)-phenyl]-cyclobutylamine 431.3 5-18

487.3 1-[4-(3-Bromo-6- phenyl-2- trifluoromethyl-imidazo[1,2-a]pyrimidin- 7-yl)-phenyl]- cyclobutylamine 397.4 5-19

430.6 1-[4-(3-Methyl-2,6- diphenyl-imidazo[1,2- a]pyrimidin-7-yl)-phenyl]-cyclobutylamine 431.2 5-20

492.6 1-[4-(2,3,6-Triphenyl- imidazo[1,2-a]pyrimidin- 7-yl)-phenyl]-cyclobutylamine 493.3 5-21

456.6 1-[4-(3-Cyclopropyl-2,6- diphenyl-imidazo[1,2- a]pyrimidin-7-yl)-phenyl]-cyclobutylamine 457.3 5-22

546.6 1-{4-[2,6-Diphenyl-3- (2,3,4-trifluoro-phenyl)-imidazo[1,2-a]pyrimidin- 7-yl]-phenyl}- cyclobutylamine 547.3 5-23

456.6 1-[4-(2,6-Diphenyl-3- propenyl-imidazo[1,2- a]pyrimidin-7-yl)-phenyl]-cyclobutylamine 457.3

Example (6-2)

{1-[4-(2-Amino-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (6-1)

A mixture of 1 (250 mg, 0.59 mmol) and 4H-[1,2,4]Triazole-3,5-diamine(58.91 mg, 0.59 mmol) in acetic acid (0.4 mL) and ethanol (1.6 mL) washeated under reflux for 6 hours. After cooling, the mixture was dilutedwith 15 mL of DCM, the combined organic phase was washed with NaHCO₃ aq.and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by prep.TLC to give 6-1. MS (ESI) m/e (M+H+) 457.3

5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine(6-2)

To the solution of 6-1 (46 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 6-2.

MS (ESI) m/e (M+H⁺) 357.3

¹H NMR (400 MHz, MeOD): δ 8.59 (s, 1H), 8.51 (dd, J=17.2 Hz,8.4 Hz,414), 7.26-7.7.20 (m, 5H), 2.64 (m, 2H), 2.41 (m, 2H), 2.52 (m, 1H),1.85 (m, 1H)

Example (6-4)

{1-[4-(2-Acetylamino-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (6-3)

To the solution of 6-1 (100 mg, 0.22 mmol) and Et₃ N (0.2 mL) DMAP (2mg) in dioxane (2 mL) was added acetyl chloride (21 mg, 0.25 mmol) andthe mixture was heated at 100° C. for 10 h. The mixture was diluted with20 mL of DCM, the combined organic phase was washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified byprep.TLC to give 64 mg of 6-3.

MS (ESI) m/e (M+H⁺) 499.4

N-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-acetamide(6-4)

To the solution of 6-3 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 6-4.

MS (ESI) m/e (M+H⁺) 399.3

¹H NMR (400 MHz, DMSO): δ 8.533 (s, 1H), 8.491 (s, 1H), 7.337 (s, 4H),7.254-7.245 (d, J=3.6 Hz, 3H), 7.189-7.172 (t, J=6.8 Hz, 2H),2.385-2.325 (q, J=24.0 Hz, 4H), 1.981-1.939 (t, J=16.8 Hz, 1H), 1.792(s, 4H)

Example (6-7)

{1-[4-(2-Bromo-6-phenyl-[1,2,4]triazo[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (6-5)

To a suspension of CuBr₂ (294 mg, 0.64 mmol) and t-BuONO (0.2 mL, 1.7mmol) in CH₃CN (15 mL) at 50.deg.C was added a solution of compound 6-1(500 mg, 1.1 mmol) in CH₃CN (8 mL) drop-wise under N₂ atmosphere and theresulting mixture was stirred for another 30 min. The mixture was cooledto room temperature and diluted with 60 mL of EA. The insoluble solidwas filtered off and the mixture was washed with brine dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography (PE: EA=5:1) to afford 275 mg of 6-5.

MS (ESI) m/e (M+H⁺) 521.4

{1-[4-(2,6-Diphenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (6-6)

A mixture of compound 6-5 (52 mg 0.1 mmol), phenyl boronic acid (19 mg,0.15 mmol), aq.Na₂ CO₃ (2M, 0.25 mmol, 0.12 mL) and Pd(dppf)Cl₂ (10 mg)in dioxane (2 mL) was heated at 100° C. in microwave system under N₂atmosphere for 30 min. After cooling, the mixture was diluted with 15 mLof DCM, the combined organic phase was washed with 0.1N HClaq and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby prep.TLC to give 26 mg of 6-6.

MS (ESI) m/e (M+H⁺) 518.1

1-[4-(2,6-Dihenyl-[1,2,4-]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine(6-7)

To the solution of 6-6 (52 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 6-7.

MS (ESI) m/e (M+H⁺) 418.1

¹H NMR (400 MHz, MeOD): δ 8.912 (s, 1H), 8.157-8.133 (q, J=9.6 Hz, 2H),7.722-7.702 (d, J=8.0 Hz, 2H), 7.601-7.580 (d, J=8.4 Hz, 2H),7.474-7.457 (d, J=6.8 Hz, 3H), 7.313-7.308 (d, J=2 Hz, 51), 2.849-2.776(m, 2H), 2.638-2.565 (m, 2H), 2.269-2.240 (m, 1H), 2.030-1.984 (m, 1H).

Example (6-9)

{1-[4-(2-Phenoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (6-8)

A mixture of 6-5 (52 mg, 0.1 mmol), Phenol (19 mg, 0.2 mmol) and K₂ CO₃(45 mg, 0.3 mmol) in DMF (1 mL) was heated at 110° C. for 10 h. Themixture was diluted with 20 mL of DCM, the combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep.TLC to give 24 mg of 6-8.

MS (ESI)m/e (M+H⁺) 534.4

1-[4-(2-Phenoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine(6-9)

To the solution of 6-8 (24 mg, 0.04 mmol) in 1 mL of DCM was added TFA(1 mL) and the mixture was stirred at room temperature for 3 h. Themixture was concentrated by evaporation and the residue was purified byprep.HPLC to give the product 6-9.

MS (ESI) m/e (M+H⁺) 434.4

¹H NMR (400 MHz, MeOD): δ 8.720 (s, 1H), 7.724-7.703 (d, J=8.4 Hz, 2H),7.622-7.600 (d, J=8.8 Hz, 2H), 7.384-7.368 (t, J=6.4 Hz, 3H),7.309-7.285 (m, 2H), 3.862-3.838 (t, J=9.6 Hz, 4H), 3.646-3.622 (t,J=8.8 Hz, 4H), 2.902-2.829 (m, 2H), 2.720-2.648 (m, 2H), 2.382-2.305 (m,1H), 2.110-2.050 (m, 1H).

Example (6-10)

1-[4-(2-Morpholin-4-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine(6-10)

A mixture of 6-5 (52 mg, 0.1 mmol), morph line (17 mg, 0.2 mmol) and Et₃N (52 mg, 0.5 mmol) in DMF (1 mL) was heated at 110° C. for 10 h. Themixture was diluted with 20 mL of DCM, the combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Thecrude product was used without purification in the following de-Bocreaction following the similar procedure from 6-8 to 6-9 to give 19 mgof 6-10 after prep.HPLC separation.

MS (ESI) m/e (M+H⁺) 427.3

¹H NMR (400 MHz, MeOD): δ 8.833 (s, 1H), 7.625-7.604 (d, J=8.4 Hz, 2H),7.524-7.503 (d, J=8.4 Hz, 2H), 7.415-7.375 (t, J=16 Hz, 2H), 7.325-7.304(m, 3H), 7.294-7.203 (m, 5H), 2.781-2.709 (m, 2H), 2.598-2.524 (m, 2H),2.274-2.183 (m, 1H), 2.000-1.931 (m, 1H).

The following examples 6-11 to 6-12 were prepared in a similar manner toExample 6-2 using the appropriate materials commercially available;examples 6-13 to 6-19 were prepared similarly to Example 6-4; examples6-20 to 6-46 were prepared similarly to Example 6-7; examples 6-47 to6-54 were prepared similarly to Example 6-9; examples 6-55 to 6-66 werereared similarly to Example 6-10.

LC/MS (ESI) found Ex. Structure MW Compound Name [M + 1]+ 6-11

341.4 1-[4-(6-Phenyl- [1,2,4]triazolo[1,5- a]pyrimidin-5-yl)-phenyl]-cyclobutylamine 342.2 6.12

355.4 1-[4-(2-Methyl-6-phenyl- [1,2,4]triazolo[1,5- a]pyrimidin-5-yl)-phenyl]-cyclobutylamine 356.2 6-13

448.6 Ethanesulfonic acid {5- [4-(1-amino-cyclobutyl)- phenyl]-6-phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-amide 449.4 6-14

496.6 N-{5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- benzenesulfonamide 497.3 6-15

460.5 N-{5-[4-(1-Amino- cyclobutyl)-phenyl)-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- benzamide 461.2 6-16

424.5 Cyclopropanecarboxylic acid {5-[4-(1-amino- cyclobutyl)-phenyl]-6-phenyl- [1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-amide 425.3 6-17

475.6 1-{5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-3- phenyl-urea 476.4 6-18

491.6 1-{5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-3- phenyl-thiourea 492.4 6-19

428.5 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- carbamic acid ethyl ester 429.36-20

448.5 1-{4-[2-(6-Methoxy- pyridin-2-yl)-6-phenyl- a]pyrimidin-5-yl]-phenyl}-cyclobutylamine 449.3 6-21

419.5 1-[4-(6-Phenyl-2- pyrazin-2-yl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 420.3 6-22

445.6 1-{4-[2-(2,3-Dimethyl- phenyl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 446.3 6-23

453.5 1-{4-[2-(3,4-Difluoro- phenyl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 454.3 6-24

449.5 1-{4-[2-(5-Fluoro-2- methyl-phenyl)-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 450.36-25

418.5 1-[4-(6-Phenyl-2- pyridin-4-yl- a]pyrimidin-5-yl)-phenyl]-cyclobutylamine 419.2 6-26

432.5 4-{5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- phenylamine 433.2 6-27

431.5 1-[4-(6-Phenyl-2-p-tolyl- [1,2,4]triazolo[1,5- a]pyrimidin-5-yl)-phenyl]-cyclobutylamine 432.2 6-28

447.5 1-{4-[2-(4-Methoxy- phenyl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 448.2 6-29

418.5 1-[4-(6-Phenyl-2- pyridin-3-yl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 419.3 6-30

447.5 1-{4-[2-(2-Methoxy- phenyl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 448.3 6-31

470.0 1-{4-[2-(3-Chloro-4- fluoro-phenyl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 471   6-32

503.5 1-{4-[2-(2-Fluoro-4- trifluoromethyl-phenyl)- 6-phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 504.36-33

471.5 1-{4-[6-Phenyl-2-(2,3,4- trifluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 472.3 6-34

477.6 1-{4-[2-(2,4-Dimethoxy- phenyl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 478.4 6-35

407.5 1-[4-(2-Furan-3-yl-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 408.2 6-36

423.5 1-[4-(6-Phenyl-2- thiophen-3-yl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 424.3 6-37

423.5 1-[4-(6-Phenyl-2- thiophen-2-yl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 424.3 6-38

497.6 1-{4-[2-(6-Methoxy- naphthalen-2-yl)-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 498.36-39

507.6 1-[4-(2-Dibenzofuran-4- yl-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 508.2 6-40

433.5 4-{5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-phenol 434.3 6-41

431.5 1-[4-(6-Phenyl-2-m- tolyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl)-phenyl]-cyclobutylamine 432.2 6-42

509.6 1-{4-[2-(4-Phenoxy- phenyl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 510.3 6-43

493.6 1-[4-(2-Biphenyl-2-yl-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 494.3 6-44

474.6 1-[4-(2-Benzothiazol-2- yl-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 425.3 6-45

418.5 1-[4-(6-Phenyl-2- pyridin-2-yl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 419.1 6-46

424.5 1-[4-(6-Phenyl-2- thiazol-2-yl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 425.3 6-47

434.5 1-{4-[6-Phenyl-2- (pyridin-4-yloxy)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 435.2 6-48

371.4 1-[4-(2-Methoxy-6- phenyl- [1,2,4]triazolo[1,5- a]pyrimidin-5-yl)-phenyl]-cyclobutylamine 372.2 6-49

433.5 1-[4-(2-Phenoxy-6- phenyl- [1,2,4]triazolo[1,5- a]pyrimidin-5-yl)-phenyl]-cyclobutylamine 434.3 6-50

387.5 1-[4-(2-Methylsulfanyl- 6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 388.1 6-51

483.6 1-{4-[2-(Naphthalen-2- yloxy)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 484.4 6-52

509.6 1-{4-[2-(Biphenyl-2- yloxy)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)- phenyl}-cyclobutylamine 510.4 6-53

484.6 1-{4-[2-(Isoquinolin-7- yloxy)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 485.3 6-54

525.6 1-{4-[2-(4-Phenoxy- phenoxy)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 526.3 6-55

472.6 1-{4-[2-(3,4-Dihydro- 2H-quinolin-1-yl)-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 472.46-56

458.6 1-{4-[2-(2,3-Dihydro- indol-1-yl)-6-phenyl- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl]- phenyl}-cyclobutylamine 459.4 6-57

370.5 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-methyl- amine 371.3 6-58

384.5 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- dimethyl-amine 385.3 6-59

433.5 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-pyridin- 3-yl-amine 434.2 6-60

412.5 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-diethyl- amine 413.2 6-61

399.5 N1-{5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- ethane-1,2-diamine 400.2 6-62

414.5 2-({5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-methyl- amino)-ethanol 415.4 6-63

460.6 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-benzyl- methyl-amine 461.3 6-64

660.7 1-[4-(2-{4-[Bis-(4- chloro-phenyl)-methyl]- piperazin-1-yl}-6-phenyl- [1,2,4]triazolo[1,5- a]pyrimidin-5-yl)- phenyl]-cyclobutylamine661.5 6-65

446.6 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-methyl- phenyl-amine 447.2 6-66

414.5 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}-(2- methoxy-ethyl)-amine 415.3

Example (7-2)

{1-[4-(2,6-Diphenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-3-hydroxy-3-methyl-cyclobutyl}-carbamicAcid Tert-butyl Ester (7-1)

A mixture of 2 (270 mg, 0.6 mmol) and5-Phenyl-4H-[1,2,4]triazol-3-ylamine (96 mg, 0.6 mmol) in acetic acid (1mL) and ethanol (4 mL) was heated under reflux for 6 hours.

After cooling, the mixture was diluted with 30 mL of DCM, the combinedorganic phase was washed with NaHCO₃ aq. and brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by prep.TLC to give7-1.

MS (ESI) m/e (M+H⁺) 547.6

3-Amino-3-[4-(2,6-diphenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol(7-2)

To the solution of 7-1 (54 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 7-2.

MS (ESI) m/e (M+H⁺) 447.6

¹H NMR (400 MHz, MeOD): δ 8.92 (s, 1H), 8.15-8.13 (m, 2H), 7.72 (dd,J=8.4 Hz, 8.8 Hz, 4H), 7.46 (m, 3H), 7.31 (s, 5H), 2.93-2.89 (d, J=14.8Hz, 2H), 2.74-2.70 (d, J=14.8 Hz, 2H), 1.49 (s, 3H)

The following compound 7-3 was prepared in a similar manner to Example7-2 using the appropriate materials commercially available.

LC/MS (ESI) found Ex. Structure MW Compound Name [M + 1]+ 7-3

371.4 3-Amino-1-methyl-3-[4-(6- phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]- cyclobutanol 372.1

5-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6-phenyl-[,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicAcid Methyl Ester (8-1)

A mixture of 1 (420 mg, 1 mmol) and5-Amino-4H-[1,2,4]triazole-3-carboxylic acid methyl ester (215 mg, 1.5mmol) in acetic acid (2.5 mL) and methanol (10 mL) was heated underreflux for 8 hours. After cooling, the mixture was diluted with 40 mL ofDCM, the combined organic phase was washed with NaHCO₃ aq. and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography to give 8-1.

MS (ESI) m/e (M+H⁺) 500.4

5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicAcid Methyl Ester (8-2)

To the solution of 8-1 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 8-2 (35 mg, yield 87.8%).

MS (ESI) m/e (M+H⁺) 400.4

¹H NMR (400 MHz, MeOD): δ 9.04 (s, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.56 (d,J=8.0 Hz, 2H), 7.31 (s, 5H), 3.95 (s, 3H), 2.74-2.81 (m, 2H), 2.56-2.63(m, 2H), 2.19 (m, 1H), 1.97 (m, 1H)

Example (8-4)

5-[4-(1-tert-Butoxycarbonylamino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicAcid (8-3)

A mixture of 8-1 (250 mg, 0.5 mmol) and LiOH (25 mg, 1.0 mmol) in THF (5mL) and H₂O (2.5 mL) was stirred at room temperature overnight. Themixture was adjusted with 2N HCl aq to pH=4 and then was extracted withEA twice. The combined organic phase was washed with H₂O and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby prep.HPLC to give 8-3.

MS (ESI) m/e (M+H⁺) 486.3

5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicAcid (8-4)

To the solution of 8-3 (49 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 8-4.

MS (ESI) m/e (M+H⁺) 386.3

¹H NMR (400 MHz, MeOD): δ 9.05 (s, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.58 (d,J=8.0 Hz, 2H), 7.34 (s, 5H), 2.66-2.83 (m, 2H), 2.59-2.66 (m, 2H),2.22-2.39 (m, 1H), 1.95-2.06 (m, 1H)

Example (8-6)

(1-{4-[2-(1-Hydroxy-1-methyl-ethyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutyl)-carbamicAcid Tert-butyl Ester (8-5)

To a solution of 8-1 (100 mg, 0.2 mmol) in 4 mL of dry THF was addedMethylmagnesium bromide (3 M THFE solution, 0.3 mL, 0.9 mmol) dropwiseat −20° C., then it was naturally warmed to 0° C. and stirred for 3 h.The resulting solution was quenched by NH₄Cl aq, the mixture wasextracted with EA twice. The combined organic phase was washed withNaHCO₃ aq. and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep.HPLC to give 8-5.

MS (ESI) m/e (M+H⁺) 500.4

2-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-propan-2-ol(8-6)

To the solution of 8-5 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 8-6 (37 mg, yield 92.5%).

MS (ESI) m/e (M+H⁺) 400.4

¹H NMR (400 MHz, MeOD): δ 8.92 (s, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.52 (d,J=8.0 Hz, 2H), 7.30-7.34 (m, 5H), 2.64-2.72 (m, 2H), 2.41-2.49 (m, 2H),2.15-2.24 (m, 1H), 1.87-1.95 (m, 1H), 1.66 (s, 6H)

Example (8-8)

{1-[4-(2-Methylcarbamoyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (8-7)

To a solution of 8-3 (243 mg, 0.5 mmol) in DMF (5 mL) was addedMethanamine HC salt (50 mg, 0.75 mmol), HOBT (73 mg, 0.5 mmol), EDCI(192 mg, 1 mmol) and TEA (125 mg, 1.25 mmol) at room temperature and themixture was stirred for overnight. The mixture was diluted with 15 mL ofH₂O, extracted with EA, the combined organic phase was washed withNaHCO₃ aq. and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep.HPLC to give 8-7.

MS (ESI)m/e (M+H⁺) 499.4

5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicAcid Methylamide (8-8)

To the solution of 8-7 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 8-8.

MS (ESI) m/e (M+H⁺) 399.4

¹H NMR (400 MHz, MeOD): δ 9.04 (s, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.59 (d,J=8.0 Hz, 2H), 7.34-7.37 (m, 5H), 3.01 (s, 3H), 2.76-2.85 (m, 2H),2.61-2.69 (m, 2H), 2.35-2.42 (m, 1H), 1.97-2.05 (m, 1H)

The following example 8-9 was prepared in a similar manner to Example8-6 using the appropriate materials commercially available; examples8-10 to 8-17 were prepared similarly to Example 8-8.

LC/MS (ESI) found Ex. Structure MW Compound Name [M + 1]+ 8-9 

523.6 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- diphenyl-methanol 524.4 8-10

384.4 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid amide 385.1 8-11

454.5 {5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}- morpholin-4-yl- methanone 455.38-12

488.6 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid phenethyl-amide 489.4 8-13

440.6 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid diethylamide 441.4 8-14

460.5 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid phenylamide 461.3 8-15

488.6 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid benzyl- methyl-amide 489.4 8-16

428.5 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid methoxy-methyl-amide 429.3 8-17

474.6 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-2- carboxylic acid methyl- phenyl-amide 475.4

{1-[4-(2,6-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (9-1)

A mixture of 1 (250 mg, 0.59 mmol) and 5-Phenyl-2H-pyrazol-3-ylamine (96mg, 0.59 mmol) in acetic acid (0.4 mL) and ethanol (1.6 mL) was heatedunder reflux for 6 hours. After cooling, the mixture was diluted with 15mL of DCM, the combined organic phase was washed with NaHCO₃ aq. andbrine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by prep.TLC to give 9-1.

MS (ESI) m/e (M+H⁺) 517.4

1-[4 (26-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine(9-2)

To the solution of 9-1 (52 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 9-2.

MS (ESI) m/e (M+H⁺) 417.4

¹H NMR (400 MHz, MeOD): δ 8.57 (s, 1H), 7.89 (d, J=7.2 Hz, 2H), 7.67 (d,J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.41-7.34 (m, 3H), 7.28-7.23 (m,5H), 2.85-2.77 (m, 2H), 2.67-2.55 (m, 2H), 2.30-2.19 (m, 1H), 2.04-1.94(m, 1H)

Example (9-4)

{1-[4-(3-Bromo-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (9-3)

To a solution of compound 9-1 (104 mg, 0.2 mmol) in CHCl₃ (5 mL) wasadded NBS (40 mg 0.22 mmol.) and the mixture was stirred at roomtemperature overnight. The mixture was diluted with 15 mL of DCM, thecombined organic phase was washed with 0.1N HClaq and brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by prep.TLCto give 83 mg of 9-3.

MS (ESI) m/e (M+H⁺) 595.9

1-4-(2,3,6-Triphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl-cyclobutylamine(9-4)

To the solution of 9-3 (60 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 9-4.

MS (ESI)m/e (M+H⁺) 495.9

¹H NMR (400 MHz, MeOD): δ 8.64 (s, 1H), 7.97 (d, J=7.2 Hz, 2H), 7.52 (d,J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.44-7.37 (m, 3H), 7.28-7.23 (m,5H), 2.71-2.59 (m, 2H), 2.40-2.25 (m, 2H), 2.19-2.06 (m, 1H), 1.90-1.75(m, 1H)

Example (9-6)

{1-[4-(2,3,6-Triphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (9-5)

A mixture of compound 9-3 (60 mg 0.1 mmol), phenyl boronic acid (19 mg,0.15 mmol), aq.Na₂ CO₃ (2M, 0.25 mmol, 0.12 mL) and Pd(DPPF)Cl₂ (10 mg)in dioxane (2 mL) was heated at 100° C. in microwave system under N₂atmosphere for 30 min. After cooling, the mixture was diluted with 15 mLof DCM, the combined organic phase was washed with 0.1N HClaq and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby prep.TLC to give 43 mg of 9-5.

MS (ESI) m/e (M+H⁺) 593.5

1-[4-(2,3,6-Triphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine(9-6)

To the solution of 9-5 (60 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1mL) and the mixture was stirred at room temperature for 3 h. The mixturewas concentrated by evaporation and the residue was purified byprep.HPLC to give the product 9-6.

MS (ESI) m/e (M+H⁺) 493.5

¹H NMR (400 MHz, MeOD): δ 8.50 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.47 (d,J=8.0 Hz, 2H), 7.42-7.38 (m, 4H), 7.31-7.21 (m, 1H), 2.77-2.65 (m, 2H),2.51-2.47 (m, 2H), 2.22-2.11 (m, 1H), 1.96-1.83 (m, 1H).

The following examples 9-8 to 9-17 were prepared in a similar manner toExample 9-2 using the appropriate materials commercially available;examples 9-18 to 9-19 were prepared similarly to Example 9-4; examples9-20 to 9-33 were prepared similarly to Example 9-6.

LC/MS (ESI) found Ex. Structure MW Compound Name [M + 1]+ 9-8 

340.4 1-[4-(6-Phenyl- pyrazolo[1,5- a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 341.2 9-9 

354.5 1-[4-(2-Methyl-6- phenyl-pyrazolo[1,5- a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 435.3 9-10

356.4 5-[4-(1-Amino- cyclobutyl)-phenyl]-6- phenyl-pyrazolo[1,5-a]pyrimidin-2-ol 357.2 9-11

430.6 1-[4-(6-Phenyl-2-p- tolyl-pyrazolo-[1,5- a]pyrimidin-5-yl)-phenyl]- cyclobutylamine 431.4 9-12

446.6 1-{4-[2-(4-Methoxy- phenyl)-6-phenyl- pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 447.4 9-13

430.6 1-[4-(6-Phenyl-2-o- tolyl-pyrazolo[1,5- a]pyrimidin-5-yl)-phenyl]- cyclobutylamine 431.4 9-14

451.0 1-{4-[2-(4-Chloro- phenyl)-6-phenyl- pyrazolo[1,5-a]pyrimidin-5-yl)- phenyl}- cyclobutylamine 452   9-15

434.5 1-{4-[2-(3-Fluoro- phenyl)-6-phenyl- pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 435.3 9-16

458.6 1-{4-[6-Phenyl-2- (2,4,6-trimethyl- phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 459.4 9-17

434.5 1-{4-[2-(4-Fluoro- phenyl)-6-phenyl- pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 435.3 9-18

374.9 1-[4-(3-Chloro-6- phenyl-pyrazolo[1,5- a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 375.7 9-19

419.3 1-[4-(3-Bromo-6- phenyl-pyrazolo[1,5- a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 420.1 9-20

493.6 1-[4-(2,6-Diphenyl-3- pyridin-4-yl- pyrazolo[1,5-a]pyrimidin-5-yl)- phenyl]- cyclobutylamine 494.4 9-21

354.5 1-[4-(3-Methyl-6- phenyl-pyrazolo[1,5- a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 355.3 9-22

528.6 1-{4-[3-(2,4-Difluoro- phenyl)-2,6-diphenyl- pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 529.4 9-23

430.6 1-[4-(3-Methyl-2,6- diphenyl-pyrazolo[1,5- a]pyrimidin-5-yl)-phenyl]- cyclobutylamine 431.4 9-24

416.5 1-[4-(3,6-Diphenyl- pyrazolo[1,5- a]pyrimidin-5-yl)- phenyl]-cyclobutylamine 417.3 9-25

418.5 1-[4-(6-Phenyl-3- pyrimidin-5-yl- pyrazolo[1,5- a]pyrimidin-5-yl)-phenyl]- cyclobutylamine 419.3 9-26

460.6 1-{4-[3-(4-Methoxy- phenyl)-2-methyl-6- phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 461.4 9-27

448.5 1-{4-[3-(2-Methoxy- pyrimidin-5-yl)-6- phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 449.3 9-28

484.5 1-{4-[6-Phenyl-3-(4- trifluoromethyl- phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 485.3 9-29

466.6 1-[4-(3-Naphthalen-1- yl-6-phenyl- pyrazolo[1,5-a]pyrimidin-5-yl)- phenyl]- cyclobutylamine 467.4 9-30

502.5 1-{4-[3-(2-Fluoro-5- trifluoromethyl- phenyl)-6-phenyl-pyrazolo[1,5- a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 503.3 9-31

469.0 1-{4-[3-(3-Chloro-4- fluoro-phenyl)-6- phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)- phenyl}- cyclobutylamine 470   9-32

492.6 1-{4-[3-(3-Fluoro-5- isopropoxy-phenyl)-6- phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 493.4 9-33

470.5 1-{4-[6-Phenyl-3- (2,3,4-trifluoro- phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}- cyclobutylamine 471.3

Example (10-2)

{(1-[4-(2,6-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-3-hydroxy-3-methyl-cyclobutyl}-carbamicAcid Tert-butyl Ester 10-1)

A mixture of 2 (450 mg, 1 mmol) and 5-Phenyl-2H-pyrazol-3-ylamine (160mg, 1 mmol) in acetic acid (2 mL) and ethanol (4 mL) was heated underreflux for 4 hours. After cooling, the mixture was diluted with 30 mL ofDCM, the combined organic phase was washed with NaHCO₃ aq. and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby flash chromoatography to give 10-1.

MS (ESI) m/e (M+H⁺) 547.5

3-Amino-3-[4-(2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol(10-2)

To the solution of 10-1 (54 mg, 0.1 mmol) in 1 mL of DCM was added TFA(1 mL) and the mixture was stirred at room temperature for 3 h. Themixture was concentrated by evaporation and the residue was purified byprep.HPLC to give the product 10-2.

MS (ESI) m/e (M+H⁺) 447.5

¹H NMR (400 MHz, MeOD): δ 8.57 (s, 1H), 7.90-7.88 (inm, 2H), 7.65 (dd,J=8.4 Hz, 8.8 Hz, 4H), 7.41-7.39 (m, 3H), 7.26 (s, 5H), 7.15 (s, 5H),2.93-2.89 (d, J=14.8 Hz, 2H), 2.73-2.69 (d, J=14.8 Hz, 2H), 1.49 (s, 3H)

Example (10-4)

{1-[4-(3-Bromo-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-3-hydroxy-3-methyl-cyclobutyl}-carbamicAcid Tert-butyl Ester (10-3)

To a solution of compound 10-1 (110 mg, 0.2 mmol) in CHCl₃ (5 mL) wasadded NBS (40 mg 0.22 mmol.) and the mixture was stirred at roomtemperature overnight. The mixture was diluted with 15 mL of DCM, thecombined organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by prep.TLC to give 81mg of 10-3.

MS (ESI) m/e (M+H⁺) 626.1

3-Amino-3-[4-(3-bromo-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol(10-4)

To the solution of 10-3 (62 mg, 0.1 mmol) in 1 mL of DCM was added TFA(1 mL) and the mixture was stirred at room temperature for 3 h. Themixture was concentrated by evaporation and the residue was purified byprep.HPLC to give the product 9-4.

MS (ESI)m/e (M+H⁺) 526.1

¹H NMR (400 MHz, MeOD): δ 8.70 (s, 1H), 7.98-7.96 (m, 2H), 7.68 (dd,J=8.4 Hz, 8.8 Hz, 4H), 7.49-7.45 (m, 3H), 7.31 (s, 5H), 2.94-2.90 (d,J=14.8 Hz, 2H), 2.74-2.70 (d, J=14.8 Hz, 2H), 1.51 (s, 3H)

Example (10-6)

{3-Hydroxy-3-methyl-1-[4-(3-methyl-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutyl}-carbamicAcid Tert-butyl Ester (10-5)

A mixture of compound 10-3 (62 mg, 0.1 mmol), Methyl boronic acid (60mg, 1 mmol), aq.Na₂ CO₃ (2M, 0.25 mmol, 0.12 mL) and Pd(DPPF)Cl₂ (10 mg)in dioxane (2 mL) was heated at 100° C. in microwave system under N₂atmosphere for 30 min. After cooling, the mixture was diluted with 15 mLof DCM, the combined organic phase was washed with 0.1N HClaq and brine,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby prep.TLC to give 23 mg of 10-5.

MS (ESI)m/e (M+H⁺) 561.5

3-Amino-1-methyl-3-[4-(3-methyl-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutanol(10-6)

To the solution of 10-5 (23 mg, 0.04 mmol) in 1 mL of DCM was added TFA(1 mL) and the mixture was stirred at room temperature for 3 h. Themixture was concentrated by evaporation and the residue was purified byprep.HPLC to give the product 10-6.

MS (ESI) m/e (M+H⁺) 461.5

¹H NMR (400 MHz, MeOD): δ 8.47 (s, 1H), 7.66-7.88 (m, 2H), 7.55 (dd,J=8.4 Hz,8.8 Hz, 4H), 7.36-7.28 (m, 3H), 7.18 (s, 5H), 2.83-2.79 (d,J=14.8 Hz, 2H), 2.60-2.59 (d, J=14.8 Hz, 2H), 2.47 (s, 3H), 1.40 (s, 3H)

The following examples 10-7 to 10-8 were prepared in a similar manner toExample 10-2 using the appropriate materials commercially available;examples 10-9 to 10-12 were prepared similarly to Example 10-6.

LC/MS (ESI) found Ex. Structure MW Compound Name [M + 1]+ 10-7 

460.6 3-Amino-1-methyl-3-[4- (6-phenyl-2-o-tolyl- pyrazolo[1,5-a]pyrimidin-5-yl)- phenyl]-cyclobutanol 461.4 10-8 

464.5 3-Amino-3-{4-[2-(4- fluoro-phenyl)-6-phenyl- pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}-1-methyl- cyclobutanol 465.3 10-9 

523.6 3-Amino-3-[4-(2,6- diphenyl-3-pyridin-3-yl- pyrazolo[1,5-a]pyrimidin-5-yl)- phenyl]-1-methyl- cyclobutanol 524.4 10-10

537.7 3-Amino-3-{4-[3-(3- amino-phenyl)-2,6- diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl]- phenyl}-1-methyl- cyclobutanol 538.5 10-11

524.6 3-Amino-3-[4-(2,6- diphenyl-3-pyrimidin-5- yl-pyrazolo[1,5-a]pyrimidin-5-yl)- phenyl]-1-methyl- cyclobutanol 525.4 10-12

539.7 3-Amino-3-{4-[3-(2- amino-pyrimidin-5-yl)- 2,6-diphenyl-pyrazolo[1,5- a]pyrimidin-5-yl]- phenyl}-1-methyl- cyclobutanol 540.5

Biological Example 1 Cloning of the Human Akt Isoforms and ΔPH-Akt1

The pS2neo vector (deposited in the ATCC on Apr. 3, 2001 as ATCCPTA-3253) was prepared as follows: The pRmHA3 vector (prepared asdescribed in Nucl. Acid Res. 16:1043-1061 (1988)) was cut with BgII anda 2734 bp fragment was isolated. The pUChsneo vector (prepared asdescribed in EMBO J. 4:167-171 (1985)) was also cut with BglII and a4029 bp band was isolated. These two isolated fragments were ligatedtogether to generate a vector termed pS2neo-1. This plasmid contains apolylinker between a metallothionine promoter and an alcoholdehydrogenase poly A addition site. It also has a neo resistance genedriven by a heat shock promoter. The pS2neo-1 vector was cut with Psp5IIand BsiWI. Two complementary oligonucleotides were synthesized and thenannealed (CTGCGGCCGC (SEQ.ID.NO.: 1) and GTACGCGGCCGCAG (SEQ.ID.NO.:2)). The cut pS2neo-1 and the annealed oligonucleotides were ligatedtogether to generate a second vector, pS2neo. Added in this conversionwas a NotI site to aid in the linearization prior to transfection intoS2 cells.

Human Akt1 gene was amplified by PCR (Clontech) out of a human spleencDNA (Clontech) using the 5′ primer:5′CGCGAATTCAGATCTACCATGAGCGACGTGGCTATTGTG 3′ (SEQ.ID.NO.: 3), and the 3′primer: 5′CGCTCTAGAGGATCCTCAGGCCGTGCTGCTGGC3′ (SEQ.ID.NO.: 4). The 5′primer included an EcoRI and BgI site. The 3′ primer included an XbaIand BamHI site for cloning purposes. The resultant PCR product wassubcloned into pGEM3Z (Promega) as an EcoRI/Xba I fragment. Forexpression/purification purposes, a middle T tag was added to the 5′ endof the full length Akt1 gene using the PCR primer:5′GTACGATGCTGAACGATATCTTCG 3′ (SEQ.ID.NO.: 5). The resulting PCR productencompassed a 5′ KpnI site and a 3′ BamHI site which were used tosubclone the fragment in frame with a biotin tag containing insect cellexpression vector, pS2neo.

For the expression of a pleckstrin homology domain (PH) deleted (Δaa4-129, which includes deletion of a portion of the Akt1 hinge region)version of Akt1, PCR deletion mutagenesis was done using the full lengthAkt1 gene in the pS2neo vector as template. The PCR was carried out in 2steps using overlapping internal primers(5′GAATACATGCCGATGGAAAGCGACGGGGCTGAAGAGATGGAGGTG 3′ (SEQ.ID.NO.: 6), and5′CCCCTCCATCTCTTCAGCCCCGTCGCTTTCCATCGGCATG TATTC 3′ (SEQ.ID.NO.: 7))which encompassed the deletion and 5′ and 3′ flanking primers whichencompassed the KpnI site and middle T tag on the 5′ end. The final PCRproduct was digested with KpnI and SmaI and ligated into the pS2neo fulllength Akt1 KpnI/SmaI cut vector, effectively replacing the 5′ end ofthe clone with the deleted version.

Human Akt3 gene was amplified by PCR of adult brain cDNA (Clontech)using the amino terminal oligo primer: 5′GAATTCAGATCTACCATGAGCGATGTTACCATTGTG 3′ (SEQ.ID.NO.: 8); and the carboxyterminal oligo primer: 5′ TCTAGATCTTATTCTCGTCCACTTGCAGAG 3′(SEQ.ID.NO.:9).

These primers included a 5′ EcoRI/BgIII site and a 3′ XbaI/BglII sitefor cloning purposes. The resultant PCR product was cloned into theEcoRI and XbaI sites of pGEM4Z (Promega). For expression/purificationpurposes, a middle T tag was added to the 5′ end of the full length Akt3clone using the PCR primer:5′GGTACCATGGAATACATGCCGATGGAAAGCGATGTTACCATTGTGAAG 3′ (SEQ.ID.NO.: 10).The resultant PCR product encompassed a 5′ KpnI site which allowed inframe cloning with the biotin tag containing insect cell expressionvector, pS2neo.

Human Akt2 gene was amplified by PCR from human thymus cDNA (Clontech)using the amino terminal oligo primer: 5′AAGCTTAGATCTACCATGAATGAGGTGTCTGTC 3′ (SEQ.ID.NO.: 11); and the carboxyterminal oligo primer: 5′GAATTCGGATCCTCACTCGCGGATGCTGGC 3′ (SEQ.ID.NO.:12). These primers included a 5′ HindIII/BglII site and a 3′ EcoRI/BamHIsite for cloning purposes. The resultant PCR product was subcloned intothe HindIII/EcoRI sites of pGem3Z (Promega). For expression/purificationpurposes, a middle T tag was added to the 5′ end of the full length Akt2using the PCR primer:5′GGTACCATGGAATACATGCCGATGGAAAATGAGGTGTCTGTCATCAAAG 3′ (SEQ.ID.NO.: 13).The resultant PCR product was subcloned into the pS2neo vector asdescribed above.

Example 2 Expression of Human Akt Isoforms and ΔPH-Akt1

The DNA containing the cloned Akt1, Akt2, Akt3 and ΔPH-Akt1 genes in thepS2neo expression vector was purified and used to transfect DrosophilaS2 cells (ATCC) by the calcium phosphate method. Pools of antibiotic(G418, 500 g/ml) resistant cells were selected.

Cell were expanded to a 1.0 L volume (˜7.0×10⁶/ml), biotin and CuSO₄were added to a final concentration of 50 M and 50 mM respectively.Cells were grown for 72 h at 27° C. and harvested by centrifugation. Thecell paste was frozen at −70° C. until needed.

Example 3 Purification of Human Akt Isoforms and ΔPH-Akt1

Cell paste from one liter of S2 cells, described in Example 2, was lysedby sonication with 50 m is 1% CHAPS in buffer A: (50 mM Tris pH 7.4, 1mM EDTA, 1 mM EGTA, 0.2 mM AEBSF, 10 g/ml benzamidine, 5 μg/ml ofleupeptin, aprotinin and pepstatin each, 10% glycerol and 1 mM DTT). Thesoluble fraction was purified on a Protein G Sepharose fast flow(Pharmacia) column loaded with 9 mg/ml anti-middle T monoclonal antibodyand eluted with 75 μM EYMPME (SEQ.ID.NO.: 14) peptide in buffer Acontaining 25% glycerol. Akt/PKB containing fractions were pooled andthe protein purity evaluated by SDS-PAGE. The purified protein wasquantitated using a standard Bradford protocol. Purified protein wasflash frozen on liquid nitrogen and stored at −70° C.

Akt and Akt pleckstrin homology domain deletions purified from S2 cellsrequired activation. Akt and Akt pleckstrin homology domain deletionswere activated (Alessi et al. Current Biology 7:261-269) in a reactioncontaining 10 nM PDK1 (Upstate Biotechnology, Inc.), lipid vesicles (10μM phosphatidylinositol-3,4,5-trisphosphate—Metreya, Inc, 100 μMphosphatidylcholine and 100 μM phosphatidylserine—Avanti Polar lipids,Inc.) and activation buffer (50 mM Tris pH7.4, 1.0 mM DTT, 0.1 mM EGTA,1.0 μM Microcystin-LR, 0.1 mM ATP, 10 mM MgCl₂, 333 μg/ml BSA and 0.1 mMEDTA). The reaction was incubated at 22° C. for 4 hours. Aliquots wereflash frozen in liquid nitrogen.

Example 4 Akt Kinase Assays

Activated Akt isoforms and pleckstrin homology domain deletionconstructs were assayed utilizing a GSK-derived biotinylated peptidesubstrate. The extent of peptide phosphorylation was determined byHomogeneous Time Resolved Fluorescence (HTRF) using a lanthanidechelate(Lance)-coupled monoclonal antibody specific for thephosphopeptide in combination with a streptavidin-linked allophycocyanin(SA-APC) fluorophore which will bind to the biotin moiety on thepeptide. When the Lance and APC are in proximity (i.e. bound to the samephosphopeptide molecule), a non-radiative energy transfer takes placefrom the Lance to the APC, followed by emission of light from APC at 665nm.

Materials Required for the Assay:

A. Activated Akt isozyme or pleckstrin homology domain deleted constructB. Akt peptide substrate: GSK3a (S21) Peptide #3928 biotin-GGRARTSSFAEPG(SEQ.ID.NO.:15), Macromolecular Resources.C. Lance labeled anti-phospho GSK3a monoclonal antibody (Cell SignalingTechnology, clone #27).D. SA-APC (Prozyme catalog no. PJ25S lot #896067).

E. Microfluor®B U Bottom Microtiter Plates (Dynex Technologies, Catalogno. 7205). F. Discovery® HTRF Microplate Analyzer, Packard InstrumentCompany.

G. 100× Protease Inhibitor Cocktail (PlC): 1 mg/ml benzamidine, 0.5mg/ml pepstatin, 0.5 mg/m leupeptin, 0.5 mg/ml aprotinin.H. 10× Assay Buffer: 500 mM HEPES, pH 7.5, 1% PEG, mM EDTA, 1 mM EGTA,1% BSA, 20 mM S-Glycerol phosphate.I. Quench Buffer: 50 mM HEPES pH 7.3, 16.6 mM EDTA, 0.1% BSA, 0.1%Triton X-100, 0.17 nM Lance labeled monoclonal antibody clone #27,0.0067 mg/ml SA-APCJ. ATP/MgCl₂ working solution: 1× Assay buffer, 1 mM DTT, 1×PIC, 125 mMKCl, 5% Glycerol, 25 mM MgCl₂, 375 TM ATPK. Enzyme working solution: 1× Assay buffer, 1 mM DTT, 1×PIC, 5%Glycerol, active Akt. The final enzyme concentrations were selected sothat the assay was in a linear response range.L. Peptide working solution: 1× Assay buffer, 1 mM DTT, 1×PIC, 5%Glycerol, 2 TM GSK3 biotinylated peptide #3928 The reaction is assembledby adding 16 TL of the ATP/MgCl₂ working solution to the appropriatewells of a 96-well microtiter plate. Inhibitor or vehicle (1.0 Tl) isadded followed by 10 Tl of peptide working solution. The reaction isstarted by adding 13 Tl of the enzyme working solution and mixing. Thereaction is allowed to proceed for 50 min and then stopped by theaddition of 60 Tl HTRF quench buffer. The stopped reactions wereincubated at room temperature for at least 30 min and then read on theDiscovery instrument.

Procedure for Streptavidin Flash Plate Assay: Step 1:

A 1 μl solution of the test compound in 100% DMSO was added to 20 μl of2× substrate solution (20 uM GSK3 Peptide, 300 μM ATP, 20 mM MgCl₂, 20μCi/ml [γ³³P]ATP, 1× Assay Buffer, 5% glycerol, 1 mM DTT, 1×PIC, 0.1%BSA and 100 mM KCl). Phosphorylation reactions were initiated by adding19 μl of 2× Enzyme solution (6.4 nM active Akt/PKB, 1× Assay Buffer, 5%glycerol, 1 mM DTT, 1×PIC and 0.1% BSA). The reactions were thenincubated at room temperature for 45 minutes.

Step 2:

The reaction was stopped by adding 170 μl of 125 mM EDTA. 200 μl ofstopped reaction was transferred to a Streptavidin Flashplate® PLUS (NENLife Sciences, catalog no. SMP103). The plate was incubated for ≧10minutes at room temperature on a plate shaker. The contents of each wellwas aspirated, and the wells rinsed 2 times with 200 μl TBS per well.The wells were then washed 3 times for 5 minutes with 200 μl TBS perwell with the plates incubated at room temperature on a platform shakerduring wash steps.

The plates were covered with sealing tape and counted using the PackardTopCount with the appropriate settings for counting [³³P] inFlashplates.

Procedure for Streptavidin Filter Plate Assay: Step 1:

The enzymatic reactions as described in Step 1 of the Streptavidin FlashPlate Assay above were performed.

Step 2:

The reaction was stopped by adding 20 μl of 7.5M GuanidineHydrochloride. 50 μl of the stopped reaction was transferred to theStreptavidin filter plate (SAM2™ Biotin Capture Plate, Promega, catalogno. V7542) and the reaction was incubated on the filter for 1-2 minutesbefore applying vacuum.

The plate was then washed using a vacuum manifold as follows: 1) 4×200μl/well of 2M NaCl; 2) 6×200 μl/well of 2M NaCl with 1% H₃PO₄; 3) 2×200μl/well of diH₂0; and 4) 2×100 μl/well of 95% Ethanol. The membraneswere then allowed to air dry completely before adding scintillant.

The bottom of the plate was sealed with white backing tape, 30 μl/wellof Microscint 20 (Packard Instruments, catalog no. 6013621) was added.The top of the plate was sealed with clear sealing tape, and the platethen counted using the Packard TopCount with the appropriate settingsfor [³³P] with liquid scintillant.

Procedure for Phosphocellulose Filter Plate Assay: Step 1:

The enzymatic reactions were performed as described in Step 1 of theStreptavidin Flash Plate Assay (above) utilizing KKGGRARTSSFAEPG(SEQ.ID.NO.: 16) as the substrate in place of biotin-GGRARTSSFAEPG.

Step 2:

The reaction was stopped by adding 20 μl of 0.75% H₃ PO₄. 50 μl ofstopped reaction was transferred to the filter plate (UNIFILTER™,Whatman P81 Strong Cation Exchanger, White Polystyrene 96 Well Plates,Polyfiltronics, catalog no. 7700-3312) and the reaction incubated on thefilter for 1-2 minutes before applying vacuum.

The plate was then washed using a vacuum manifold as follows: 1) 9×200μl/well of 0.75% H₃ PO₄; and 2) 2×200 μl/well of diH₂0. The bottom ofthe plate was sealed with white backing tape, then 30 μl/well ofMicroscint 20 was added. The top of the plate was sealed with clearsealing tape, and the plate counted using the Packard TopCount with theappropriate settings for [³³P] and liquid scintillant.

PKA Assay:

Each individual PKA assay consists of the following components:A. 5×PKA assay buffer (200 mM Tris pH7.5, 100 mM MgCl₂, 5 mM9-mercaptoethanol, 0.5 mM EDTA)B. 50 μM stock of Kemptide (Sigma) diluted in waterC. ³³P-ATP prepared by diluting 1.0 μl ³³P-ATP [10 mCi/ml]into 200 TI ofa 50 μM stock of unlabeled ATPD. 10 μl of a 70 nM stock of PKA catalytic subunit (UBI catalog #14-114)diluted in 0.5 mg/ml BSAE. PKA/Kemptide working solution: equal volumes of 5×PKA assay buffer,Kemptide solution and PKA catalytic subunit.

The reaction is assembled in a 96 deep-well assay plate. The inhibitoror vehicle (10 Tl) is added to 10 Tl of the ³³P-ATP solution. Thereaction is initiated by adding 30 Tl of the PKA/Kemptide workingsolution to each well. The reactions were mixed and incubated at roomtemperature for 20 min. The reactions were stopped by adding 50 Tl of100 mM EDTA and 100 mM sodium pyrophosphate and mixing.

The enzyme reaction product (phosphorylated Kemptide) was collected onp81 phosphocellulose 96 well filter plates (Millipore). To prepare theplate, each well of a p81 filter plate was filled with 75 mM phosphoricacid. The wells were emptied through the filter by applying a vacuum tothe bottom of the plate. Phosphoric acid (75 mM, 170 μl) was added toeach well. A 30 μl aliquot from each stopped PKA reaction was added tocorresponding wells on the filter plate containing the phosphoric acid.The peptide was trapped on the filter following the application of avacuum and the filters were washed 5 times with 75 mM phosphoric acid.After the final wash, the filters were allowed to air dry. Scintillationfluid (30 μl) was added to each well and the filters counted on aTopCount (Packard).

PKC Assay:

Each PKC assay consists of the following components:A. 10×PKC co-activation buffer: 2.5 mM EGTA, 4 mM CaCl₂B. 5×PKC activation buffer: 1.6 mg/ml phosphatidylserine, 0.16 mg/mldiacylglycerol, 100 mM Tris pH 7.5, 50 mM MgCl₂, 5 mM $-mercaptoethanolC. ³³P-ATP prepared by diluting 1.0 μl ³³P-ATP [10 mCi/ml]into 100p of a100 μM stock of unlabeled ATPD. Myelin basic protein (350 μg/ml, UBI) diluted in waterE. PKC (50 ng/ml, UBI catalog #14-115) diluted into 0.5 mg/ml BSAF. PKC/Myelin Basic Protein working solution: Prepared by mixing 5volumes each of PKC co-activation buffer and Myelin Basic protein with10 volumes each of PKC activation buffer and PKC.

The assays were assembled in 96 deep-well assay plates. Inhibitor orvehicle (10 Tl) was added to 5.0 ul of ³³P-ATP. Reactions were initiatedwith the addition of the PKC/Myelin Basic Protein working solution andmixing. Reactions were incubated at 30° C. for min. The reactions werestopped by adding 50 Tl of 100 mM EDTA and 100 mM sodium pyrophosphateand mixing. Phosphorylated Mylein Basic Protein was collected on PVDFmembranes in 96 well filter plates and quantitated by scintillationcounting.

Compounds of the instant invention described in the Schemes and Tableswere tested in the assay described above and were found to have ICs₅₀ of≦50 μM against one or more of Akt1, Akt2 and Akt3.

Example 5 Cell Based Assays to Determine Inhibition of Akt/PKB

Cells (for example LnCaP or a PTEN(—tumor cell line with activatedAkt/PKB) were plated in 100 mM dishes. When the cells were approximately70 to 80% confluent, the cells were referred with 5 mls of fresh mediaand the test compound added in solution. Controls included untreatedcells, vehicle treated cells and cells treated with either LY294002(Sigma) or wortmanin (Sigma) at 20 μM or 200 nM, respectively. The cellswere incubated for 2, 4 or 6 hrs, and the media removed, the cells werewashed with PBS, scraped and transferred to a centrifuge tube. They werepelleted and washed again with PBS. Finally, the cell pellet wasresuspended in lysis buffer (20 mM Tris pH8, 140 mM NaCl, 2 mM EDTA, 1%Triton, 1 mM Na Pyrophosphate, 10 mM 8-Glycerol Phosphate, 10 mM NaF,0.5 mm NaVO₄, 1±M Microsystine, and 1× Protease Inhibitor Cocktail),placed on ice for 15 minutes and gently vortexed to lyse the cells. Thelysate was spun in a Beckman tabletop ultra centrifuge at 100,000×g at4° C. for 20 min. The supernatant protein was quantitated by a standardBradford protocol (BioRad) and stored at −70° C. until needed.

Proteins were immunoprecipitated (IP) from cleared lysates as follows:For Akt1/PKBI, lysates are mixed with Santa Cruz sc-7126 (D-17) in NETN(100 mM NaCl, 20 mM Tris pH 8.0, 1 mM EDTA, 0.5% NP-40) and Protein A/GAgarose (Santa Cruz sc-2003) was added. For Akt2/PKBq, lysates weremixed in NETN with anti-Akt2 agarose (Upstate Biotechnology #16-174) andfor Akt3/PKBK, lysates were mixed in NETN with anti-Akt3 agarose(Upstate Biotechnology #16-175). The IPs were incubated overnight at 4°C., washed and separated by SDS-PAGE.

Western blots were used to analyze total Akt, pThr308 Akt1, pSer473Akt1, and corresponding phosphorylation sites on Akt2 and Akt3, anddownstream targets of Akt using specific antibodies (Cell SignalingTechnology): Anti-Total Akt (cat. no. 9272), Anti-Phopho Akt Serine 473(cat. no, 9271), and Anti-Phospho Akt Threonine 308 (cat. no. 9275).After incubating with the appropriate primary antibody diluted inPBS+0.5% non-fat dry milk (NFDM) at 4° C. overnight, blots were washed,incubated with Horseradish peroxidase (HRP)-tagged secondary antibody inPBS+0.5% NFDM for 1 hour at room temperature. Proteins were detectedwith ECL Reagents (Amersham/Pharmacia Biotech RPN2134).

Example 6 Heregulin Stimulated Akt Activation

MCF7 cells (a human breast cancer line that is PTEN^(+/+)) were platedat 1×10⁶ cells per 100 mM plate. When the cells were 70-80% confluent,they were referred with 5 ml of serum free media and incubatedovernight. The following morning, compound was added and the cells wereincubated for 1-2 hrs, after which time heregulin was added (to inducethe activation of Akt) for 30 minutes and the cells were analyzed asdescribed above.

Example 7 Inhibition Of Tumor Growth

In vivo efficacy of an inhibitor of the growth of cancer cells may beconfirmed by several protocols well known in the art.

Human tumor cell lines which exhibit a deregulation of the PI3K pathway(such as LnCaP, PC3, C33a, OVCAR-3, MDA-MB-468, A2780 or the like) areinjected subcutaneously into the left flank of 6-10 week old female nude(also male mice [age 10-14 weeks]are used for prostate tumor xenografts[LnCaP and PC3]) mice (Harlan) on day 0. The mice are randomly assignedto a vehicle, compound or combination treatment group. Dailysubcutaneous administration begins on day 1 and continues for theduration of the experiment. Alternatively, the inhibitor test compoundmay be administered by a continuous infusion pump. Compound, compoundcombination or vehicle is delivered in a total volume of 0.2 ml. Tumorsare excised and weighed when all of the vehicle-treated animalsexhibited lesions of 0.5-1.0 cm in diameter, typically 4 to 5.5 weeksafter the cells were injected. The average weight of the tumors in eachtreatment group for each cell line is calculated.

Example 8 Spot Multiplex Assay

This procedure describes a sandwich immunoassay used to detect multiplephosphorylated proteins in the same well of a 96 well format plate. Celllysates are incubated in 96-well plates on which different captureantibodies are placed on spatially distinct spots in the same well.Phoshorylation-specific rabbit polyclonal antibodies are added and thecomplex is detected by an anti-rabbit antibody labeled with anelectrochemiluminescent tag.

96-Well LNCaP plates +/−Compounds:

Spin in Beckman J6 1200 rpm 10 min, aspirate media. Add 50 μl/well: TBS(Pierce #28376-20 mM Tris pH 7.5, 150 mM NaCl)+1% Triton X-100+Proteaseand Phosphatase Inhibitors. Wrap in plastic wrap, place in −70° C.freezer until completely frozen. Block Multiplex Plates (Meso ScaleDiscovery, Gaithersburg, Md.) with 3% Blocker A in 1× Tris Wash Buffer,1501S/well. Cover with plate sealer, incubate on Micromix shaker RT 2 h(minimum). Wash with 1×RCM 51 (TTBS). Thaw cell lysate plates on ice,add 40 μl lysate/well into blocked plates. Cover with plate sealer,incubate on Micromix shaker 4° C. O/N, Wash with 1×RCM 51. DiluteSecondary Antibodies in 1% Blocker A in 1× Tris Wash Buffer: Antiphospho AKT (T308), Anti phospho Tuberin (T1462), alone or incombination. Add 251/well, cover with plate sealer, incubate on Micromixshaker RT 3 h. Wash with 1×RCM 51. Dilute Ru-GAR in 1% Blocker A in 1×Tris Wash Buffer. Add 25 μl/well, cover with plate sealer, incubate onMicromix shaker RT 1 h. Wash with 1×RCM 51. Dilute 4× Read Buffer T to1× with Water, add 200 μl diluted Read Buffer/well Read on Sector 6000Imager.

Protease and Phosphatase Inhibitors:

Microcystin-LR, Calbiochem #475815 to 1 μM final concentration(stock=500 μM)

Calbiochem #524624, 100× Set I Calbiochem #524625, 100× Set IICalbiochem #539134, 100× Set II Anti Phospho AKT (T308): Cell SignalingTechnologies #9275 Anti Phospho Tuberin (T1462): Covance AffinityPurified (Rabbits MS 2731/2732)

Ru-GAR=Ruthenviated Goat anti Rabbit

10× Tris Wash Buffer, Blocker A and 4× Read Buffer T 10×RCM 51 (10×TTBS,RCM 51) 1×=20 mM Tris pH 7.5, 140 mM NaCl, 0.1% Tween-20 Example 9Cell-Based (In-Vivo) Assay

This procedure describes a cell-based (in vivo) activity assay for theAkt serine/threonine kinase. Activated endogenous Akt is capable ofphosphorylating a specific Akt substrate (GSK3β) peptide which isbiotinylated. Detection is performed by Homogeneous Time ResolvedFluorescence (HTRF) using a Europium Kryptate [Eu(K)]coupled antibodyspecific for the phosphopeptide and streptavidin linked XL665fluorophore which will bind to the biotin moiety on the peptide. Whenthe [Eu(K)] and XL665 are in proximity (i.e. bound to the samephosphopeptide molecule) a non-radiative energy transfer takes placefrom the Eu(K) to the XL665, followed by emission of light from XL665 at665 nm.

The assay can be used to detect inhibitors of all three Akt isozymes(Akt1, Akt2, and Akt3) from multiple different species if specificantibodies to each exist.

Materials and Reagents

A. Cell Culture Microtiter Flat Bottom 96 well plates, Corning Costar,Catalog no. 3598B. Reacti-Bind Protein A Coated 96-well plates, Pierce, Catalog no15130.C. Reacti-Bind Protein G Coated 96-well plates, Pierce, Catalog no15131.

D. Micromix 5 Shaker. E. Microfluor®B U Bottom Microtiter Plates, DynexTechnologies, Catalog no. 7205.

F. 96 Well Plate Washer, Bio-Tek Instruments, Catalog no. EL 404.

G. Discovery® HTRF Microplate Analyzer, Packard Instrument Company.Buffer Solutions

A. IP Kinase Cell Lysis Buffer: 1×TBS; 0.2% Tween 20; 1× ProteaseInhibitor Cocktail III (Stock is 100×, Calbiochem, 539134); 1×Phosphatase Inhibitor Cocktail I (Stock is 100×, Calbiochem, 524624);and 1× Phosphatase Inhibitor Cocktail II (Stock is 100×, Calbiochem,524625).

B. 10× Assay Buffer: 500 mM Hepes pH 7.5; 1% PEG; 1 mM EDTA; 1 mM EGTA;and 20 mM P-glycerophosphate. C. IP Kinase Assay Buffer: 1× AssayBuffer; 50 mM KCl; 150 μM ATP; 10 mM MgCl₂; 5% Glycerol; 1 mM DTT; 1Tablet Protease Inhibitor Cocktail per 50 ml Assay Buffer; and 0.1% BSA

D. GSK3β Substrate Solution: IP Kinase Assay Buffer; and 500 nMBiotinylated GSK3P peptide.

E. Lance Buffer: 50 mM Hepes pH 7.5; 0.1% BSA; and 0.1% Triton X-100. F.Lance Stop Buffer: Lance Buffer; and 33.3 mM EDTA.

G. Lance Detection Buffer: Lance Buffer; 13.3 μg/ml SA-APC; and 0.665 nMEuK Ab a-phospho (Ser-21) GSK3B

Multi-Step Immunoprecipitation Akt Kinase Assay Dav

A. Seed C33a cells Step: Plate 60,000 C33a cells/well in 96 wellmicrotiter plate.B. Incubate cells overnight at 37° C.

Day 2

D. Compound Addition Step: Add compounds in fresh media (alpha-MEM/10%FBS, room temp) to 96 well plate from above and incubate for 5 hrs intissue culture incubator.E. Cell Lysis Step: Aspirate media and add 100 μl of IP Kinase CellLysis Buffer.F. Freeze 96 well microtiter plate at −70° C. (NOTE: This step can bedone for a minimum of 1 hour or overnight.)

Day 3

G. Coat Protein A/G 96 well plate Step: Add appropriate concentration ofα-Akt antibody (Akt1, Akt2, or Akt3) in a 100 μl of PBS to the followingwells:

-   -   α-Akt 1 (20 ng/well/100 ul) B2>>>>>>B10/rows B-G/Akt1 plate    -   α-Akt 2 (50 ng/well/100 ul) B2>>>>>>B10/rows B-G/Akt2 plate    -   Rabbit-IgG (150 ng/well/100 ul): B11-G11 on every plate (Akt1        and Akt2)        H. Incubate in the cold room (+4° C.) for 4 hours on the        Micromix 5 (Form 20; Attitude 2) (NOTE: Attitude depends on        which Micromix 5 machine).        I. Aspirate off α-Akt antibody solution and add 100 μl of PBS to        each well.        J. Akt Immunoprecipitation Step: To the 100 μl of PBS from        Step (I) add 5 μl of thawed cell lystate for Akt1 plates and 10        μl of thawed cell lysate for Akt2 plates. NOTE: Thaw cell lysate        on ice. Mix thawed lysate by pipetting up & down 10× before        transferring to antibody plates. Keep the cell lysate plates on        ice. After transfer of cell lysate to the antibody plates        refreeze the cell lysate plates at −70° C.        K. Incubate in the cold room (+4° C.) overnight on Micromix 5        shaker (form 20, attitude 3).

Day 4

L. Immunoprecipitation Plate Wash Step: Wash 96 well plates 1× with TTBS(RCM 51, 1×=2 cycles) using the 96-Well Plate Washer. Fill wells withTTBS and incubate for 10 minutes. Wash 96 well plates 2× with TTBS.(NOTE: Prime plate washer before use: 1. Check buffer reservoirs, makingsure they are full and 2. empty waste containers.M. Manual Plate Wash Step: Add 180 μl of IP Kinase Assay buffer.N. Start Akt Enzyme Reaction: Aspirate supernatant. Add 60 μl of GSK3βSubstrate Solution.O. Incubate for 2.5 hours on Micromix 5 shaker@RT. NOTE: Time ofincubation should be adjusted so that the ratio of Column 10/Column 11is not >10.P. Combine 30 μl of Lance Detection Buffer with 30 μl of Lance StopBuffer (60 μl total/well) and add to Microfluor U bottom 96 well blackplates.Q. Stop Akt Enzyme Reaction: Transfer 40 μl of Akt Enzyme Reaction Mixfrom Protein A/G 96 well plate from Step (O) to Microfluor U bottom 96well black plates from Step (P).U. Incubate at room temperature for 1-2 hrs on Micromix 5 shaker (form20, attitude 3), then read with the Discovery HTRF Microplate Analyzerusing Akt program.

IP Kinase Cell Lysis Buffer

100 μl per well

8 ml 45 ml (1 Plate) (6 Plates) 1X TBS 7744 μl NA Tween 20 20 μl NA 1XProtease Inhibitor Cocktail III 80 μl NA 1X Phosphatase InhibitorCocktail 450 μl I 80 μl 450 μl 1X Phosphatase Inhibitor Cocktail 450 μlII 80 μl Microcystin LR (500X) 90 μl

IP Kinase Assay Buffer

100 μl per well

8 ml 50 ml (1 Plate) (3 Plates) 10X Assay Buffer 800 μl 5 ml 1 M KCl 400μl 2.5 ml 250 mM ATP 4.8 μl 30 μl 1M MgCl₂ 80 ul 500 μl Glycerol 400 μl2.5 ml 1M DTT 8 μl 50 μl Protease Inhibitor Cocktail 1 tablet/50 ml 110% BSA 80 μl 500 μl di dH₂0 6227.2 μl 38.9 ml

GSK3β Substrate Solution

60 μl per well

5 ml (1 Plate) 7 ml IP Kinase Assay Buffer 5 ml — 1 mM GSK3β peptide 2.5ul 3.5 ul

Lance Stop Buffer

30 μl per well

3 ml (1 Plate) 5 m1 5 ml 1X Lance Buffer 2800.2 μl EDTA 0.5 M 199.8 μl

Lance Detection Buffer

30 μl per well

3 ml (1 Plate) 5 ml SA-APC (1 mg/ml in ddH2O, 40 μl 66.7 μl dilute1/75.2 in Lance Buffer) EuK Ab a-phospho (Ser 2.7 μl 4.5 μl 21)GSK3β(680 nM, dilute 1/1133 in Lance Buffer)

1. A compound according to Formula B:

wherein, A and B are independently selected from C or N, wherein atleast one of A and B is N; J and K are independently selected from C orN, wherein J and K are optionally substituted with R¹; X, Y and Z areindependently selected from C and N, wherein X, Y and Z are optionallysubstituted with R¹; a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; R¹ isindependently selected from (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)(C₁-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₁-C₁₀)alkynyl,(C═O)_(a)O_(b)(C₃-C₁₀)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₁₀)alkyl,S(O)_(m)(C₁-C₁₀)alkenyl, S(O)_(m)(C₁-C₁₀)alkynyl,S(O)_(m)(C₃-C₉)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R⁶; R³ and R^(3′) are independently selectedfrom H, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkenyl, (C₁-C₁₀)alkynyl,(C₃-C₁₀)cycloalkyl, aryl, heteroaryl, heterocyclcyl, (C═O)NR⁷R⁸, halo,OH, CF₃, CO₂H, CN, and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl and heterocyclyl are optionally substituted with one ormore substituents selected from H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl,(C₁-C₄)alkynyl, (C₃-C₁₀)cycloalkyl, halo, OH, CF₃, CO₂H, CN, phenyl andNR⁷R⁸, or R³ and R^(3′) can be taken together to form a(C₃-C₁₀)cycloalkyl, said cycloalkyl is optionally substituted with oneor more substituents selected from H, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkenyl,(C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl, aryl, heteroaryl, heterocyclcyl,(C═O)NR⁷R⁸, halo, OH, CF₃, CO₂H, CN, phenyl and NH₂, said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl arefurther optionally substituted with one or more substituents selectedfrom H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl,halo, OH, CF₃, CO₂H, CN, phenyl and NR⁷R⁸; R⁶ is selected from(C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)O_(b)(C₁-C₆)alkenyl,(C═O)_(a)O_(b)(C₁-C₆)alkynyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heteroaryl,(C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃, CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸,S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl, S(O)_(m)(C₁-C₄)alkenyl,S(O)_(m)(C₁-C₄)alkynyl, S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl,S(O)_(m)-heteroaryl, and S(O)_(m)-heterocyclyl said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionallysubstituted with one or more substituents selected from R^(6a); R^(6a)is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂; R⁷ and R⁸ are independentlyselected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, N(R^(b))₂, (C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)N(R^(b))₂,S(O)_(m)(C₁-C₆)alkyl, S(O)_(m)(C₁-C₆)alkenyl, S(O)_(m)(C₁-C₆)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a), or R⁷ and R⁸ can be taken together toform a (C₃-C₁₀)cycloalkyl, said cycloalkyl is optionally substitutedwith one or more substituents selected from H, (C₁-C₁₀)alkyl,(C₁-C₁₀)alkenyl, (C₁-C₁₀)alkynyl, (C₃-C₁₀)cycloalkyl, aryl, heteroaryl,heterocyclcyl, (C═O)NR⁷R⁸, halo, OH, CF₃, CO₂H, CN, and NR⁷R⁸; and R^(b)is independently selected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₁₀)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl areoptionally substituted with one or more substituents selected from(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, halo, OH, CF₃, CO₂H, CN,phenyl and NH₂; or a tautomer thereof; or a pharmaceutically acceptablesalt or a stereoisomer thereof.
 2. A compound according to Formula B ofClaim 1, wherein,

is selected from:

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; R¹ is independently selectedfrom H, (C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)O_(b)(C₁-C₆)alkenyl,(C═O)_(a)O_(b)(C₁-C₆)alkynyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heteroaryl,(C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃, CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸,S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl, S(O)_(m)(C₁-C₄)alkenyl,S(O)_(m)(C₁-C₄)alkynyl, S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl,S(O)_(m)-heteroaryl, and S(O)_(m)-heterocyclyl, said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionallysubstituted with one or more substituents selected from R⁶; R³ andR^(3′) are independently selected from H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl,(C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H, CN, phenyl andNH₂, said alkyl, alkenyl, alkynyl, cycloalkyl and phenyl are optionallysubstituted with one or more substituents selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H,CN, phenyl and NH₂, or R³ and R^(3′) can be taken together to form a(C₃-C₅)cycloalkyl, said cycloalkyl is optionally substituted with one ormore substituents selected from H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl,(C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H, CN, phenyl andNH₂; R⁶ is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C—O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl,S(O)_(m)(C₁-C₄)alkenyl, S(O)_(m)(C₁-C₄)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a); R^(6a) is selected from(C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)O_(b)(C₁-C₆)alkenyl,(C═O)_(a)O_(b)(C₁-C₆)alkynyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heteroaryl,(C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃, CO₂H, CN and NH₂, saidalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclylare optionally substituted with one or more substituents selected from(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, halo, OH, CF₃, CO₂H, CN,phenyl and NH₂; R⁷ and R⁸ are independently selected from H,(C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)O_(b)(C₁-C₆)alkenyl,(C═O)_(a)O_(b)(C₁-C₆)alkynyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heteroaryl,(C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃, CO₂H, CN, N(R^(b))₂,(C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)N(R^(b))₂, S(O)_(m)(C₁-C₆)alkyl,S(O)_(m)(C₁-C₆)alkenyl, S(O)_(m)(C₁-C₆)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a); and R^(b) is independently selectedfrom H, (C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)O_(b)(C₁-C₆)alkenyl,(C═O)_(a)O_(b)(C₁-C₆)alkynyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C—O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heteroaryl and(C═O)_(a)O_(b)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl and heterocyclyl are optionally substituted with one ormore substituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, halo, OH, CF₃, CO₂H, CN, phenyl and NH₂; or a tautomerthereof; or a pharmaceutically acceptable salt or a stereoisomerthereof.
 3. A compound according to Formula B of Claim 1, wherein,

is selected from

a is or 1; b is 0 or 1; m is 0, 1 or 2;n is 0, 1, 2 or 3; R¹ isindependently selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸, S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl,S(O)_(m)(C₁-C₄)alkenyl, S(O)_(m)(C₁-C₄)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R⁶; R³ and R^(3′) are independently selectedfrom H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl, (C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂, said alkyl, alkenyl, alkynyl,cycloalkyl and phenyl are optionally substituted with one or moresubstituents selected from H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl,(C₁-C₄)alkynyl, (C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H, CN, phenyl andNH₂, or R³ and R^(3′) can be taken together to form a (C₃-C₅)cycloalkyl,said cycloalkyl is optionally substituted with one or more substituentsselected from H, (C₁-C₄)alkyl, (C₁-C₄)alkenyl, (C₁-C₄)alkynyl,(C₃-C₅)cycloalkyl, halo, OH, CF₃, CO₂H, CN, phenyl and NH₂; R⁶ isselected from (C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)O_(b)(C₁-C₆)alkenyl,(C═O)_(a)O_(b)(C₁-C₆)alkynyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heteroaryl,(C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃, CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸,S(O)_(m)NR⁷R⁸, S(O)_(m)(C₁-C₄)alkyl, S(O)_(m)(C₁-C₄)alkenyl,S(O)_(m)(C₁-C₄)alkynyl, S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl,S(O)_(m)-heteroaryl, and S(O)_(m)-heterocyclyl said alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionallysubstituted with one or more substituents selected from R^(6a); R^(6a)is selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN and NH₂, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,halo, OH, CF₃, CO₂H, CN, phenyl and NH₂; R⁷ and R⁸ are independentlyselected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl,(C═O)_(a)O_(b)(C₁-C₆)alkenyl, (C═O)_(a)O_(b)(C₁-C₆)alkynyl,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)-heteroaryl, (C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃,CO₂H, CN, N(R^(b))₂, (C═O)N(R^(b))₂, (C═S)N(R^(b))₂, S(O)_(m)N(R^(b))₂,S(O)_(m)(C₁-C₆)alkyl, S(O)_(m)(C₁-C₆)alkenyl, S(O)_(m)(C₁-C₆)alkynyl,S(O)_(m)(C₃-C₈)cycloalkyl, S(O)_(m)-aryl, S(O)_(m)-heteroaryl, andS(O)_(m)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heteroaryl and heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a); and R^(b) is independently selectedfrom H, (C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)O_(b)(C₁-C₆)alkenyl,(C═O)_(a)O_(b)(C₁-C₆)alkynyl, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)-heteroaryl and(C═O)_(a)O_(b)-heterocyclyl, said alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl and heterocyclyl are optionally substituted with one ormore substituents selected from (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, halo, OH, CF₃, CO₂H, CN, phenyl and NH₂; or a tautomerthereof; or a pharmaceutically acceptable salt or a stereoisomerthereof.
 4. A compound according to Formula B of Claim 1, wherein,

is selected from

a is 0 or I; b is 0 or 1; m is 0, 1 or 2; n is 0, 1 or 2; R¹ isindependently selected from (C═O)_(a)O_(b)(C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₃-C₈)cycloalkyl, O_(b)-aryl, O_(b)-heteroaryl,(C═O)_(a)O_(b)-heterocyclyl, halo, OH, CF₃, CO₂H, CN, NR⁷R⁸, (C═O)NR⁷R⁸,S(O)_(m)(C₁-C₄)alkyl, said alkyl, alkenyl, cycloalkyl, aryl, heteroaryland heterocyclyl are optionally substituted with one or moresubstituents selected from R⁶; R³ and R^(3′) are H, or R³ and R^(3′) canbe taken together to form cyclobutyl, said cyclobutyl is optionallysubstituted with one or more substituents selected from H, OH, methyland cyclopropyl; R⁶ is selected from O_(b)(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, O_(b)-aryl, halo, OH, CF₃, NR⁷R⁸, said alkyl andcycloalkyl are optionally substituted with one or more substituentsselected from R^(6a); R^(6a) is selected from O_(b)(C₁-C₆)alkyl, aryl,OH and NH₂, said alkyl and aryl are optionally substituted with one ormore substituents selected from halo; R⁷ and R⁸ are independentlyselected from H, (C═O)_(a)O_(b)(C₁-C₆)alkyl, (C═O)_(a)(C₃-C₈)cycloalkyl,(C═O)_(a)-aryl, heterocyclyl, (C═O)N(R^(b))₂, (C═S)N(R^(b))₂,S(O)_(m)(C₁-C₆)alkyl, and S(O)_(m)-aryl, said alkyl, cycloalkyl, aryland heterocyclyl are optionally substituted with one or moresubstituents selected from R^(6a); and R^(b) is independently selectedfrom H, (C₁-C₆)alkyl and aryl; or a tautomer thereof; or apharmaceutically acceptable salt or a stereoisomer thereof.
 5. Acompound which is selected from:1-[4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine;1-[4-(2-isopropyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine;1-[4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine;1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine;3-amino-3-[4-(3,6-diphenylimidazo[1,2-a]pyrimnidin-7-yl)phenyl]-1-methylcyclobutanol;3-amino-1-methyl-3-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanol;1-[4-(2-methyl-3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]cyclobutanamine;3-amino-1-methyl-3-[4-(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyobubutanol;3-amino-1-methyl-3-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol;1-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine;1-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanamine;3-amino-1-methyl-3-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]cyclobutanol;1-[4-(3,6-diphenylimidazo[1,2-a]pyrimidin-7-yl)phenyl]methanamine;1-[4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)phenyl]methanamine;1-[4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)phenyl]methanamine;4-(6-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-benzylamine;3-Amino-1-cyclopropyl-3-[4-(6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutanol;4-(6-Phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-benzylamine;1-[4-(6-Phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(3-Bromo-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-{4-[3-(2-Methoxy-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carbonitrile;7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-3-carboxylicacid amide;1-[4-(3-Chloro-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(3-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-{4-[3-(2-cyclopropyl-vinyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;1-[4-(2,6-Diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(3-Bromo-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;1-[4-(2,6-Diphenyl-3-vinyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(2-Ethyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-2-trifluoromethyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylicacid ethyl ester;7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylicacid;7-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylicacid methyl ester;1-{4-[2-(4-Fluoro-phenyl)-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;1-[4-(6-Phenyl-2-p-tolyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(3-Bromo-6-phenyl-2-trifluoromethyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(3-Methyl-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine1-[4-(2,3,6-Triphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-[4-(3-cyclopropyl-2,6-diphenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;1-{4-[2,6-Diphenyl-3-(2,3,4-trifluoro-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-phenyl}-cyclobutylamine;1-[4-(2,6-Diphenyl-3-propenyl-imidazo[1,2-a]pyrimidin-7-yl)-phenyl]-cyclobutylamine;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine;N-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-acetamide;1-[4-(2,6-Diphenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2-Phenoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2-Morpholin-4-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2-Methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;Ethanesulfonicacid{5-[4-(1-amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-amide;N-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-benzenesulfonamide;N-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-benzamide;Cyclopropanecarboxylicacid{5-[4-(1-amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-amide;1-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-3-phenyl-urea;1-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-3-phenyl-thiourea;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-carbamicacid ethyl ester;1-{4-[2-(6-Methoxy-pyridin-2-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(6-Phenyl-2-pyrazin-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(2,3-Dimethyl-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(3,4-Difluoro-phenyl)-6-phenyl-[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(5-Fluoro-2-methyl-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(6-Phenyl-2-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;4-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-phenylamine;1-[4-(6-Phenyl-2-p-tolyl-[1,2,4]triazolo[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(4-Methoxy-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(6-Phenyl-2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(2-Methoxy-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(3-Chloro-4-fluoro-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-6-phenyl-[,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[6-Phenyl-2-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(2,4-Dimethoxy-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(2-Furan-3-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-2-thiophen-3-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-2-thiophen-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(6-Methoxy-naphthalen-2-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(2-Dibenzofuran-4-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;4-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-phenol;1-[4-(6-Phenyl-2-m-tolyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(4-Phenoxy-phenyl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(2-Biphenyl-2-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2-Benzothiazol-2-yl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-2-thiazol-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[6-Phenyl-2-(pyridin-4-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(2-Methoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2-Phenoxy-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2-Methylsulfanyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(Naphthalen-2-yloxy)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(Biphenyl-2-yloxy)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(Isoquinolin-7-yloxy)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(4-Phenoxy-phenoxy)-6-phenyl-1,2,4]triazol[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(3,4-Dihydro-2H-quinolin-1-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(2,3-Dihydro-indol-1-yl)-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-methyl-amine;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-dimethyl-amine;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-pyridin-3-yl-amine;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-diethyl-amine;N1-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-ethane-1,2-diamine;2-({5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-methyl-amino)-ethanol;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-benzyl-methyl-amine;1-[4-(2-{4-[Bis-(4-chloro-phenyl)-methyl]-piperazin-1-yl}-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo1,5-a]pyrimidin-2-yl}-methyl-phenyl-amine;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-(2-methoxy-ethyl)-amine;3-Amino-3-[4-(2,6-diphenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol;3-Amino-1-methyl-3-[4-(6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutanol;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid methyl ester;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid;2-{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-propan-2-ol;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid methylamide;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-diphenyl-methanol;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid amide;{5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-morpholin-4-yl-methanone;5-[4-(1-Amino-cyclobutyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid phenethyl-amide;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid diethylamide;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid phenylamide;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid benzyl-methyl-amide;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid methoxy-methyl-amide;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylicacid methyl-phenyl-amide;1-[4-(2,6-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2,3,6-Triphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2,3,6-Triphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2-Methyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;5-[4-(1-Amino-cyclobutyl)-phenyl]-6-phenyl-pyrazolo[1,5-a]pyrimidin-2-ol;1-[4-(6-Phenyl-2-p-tolyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(4-Methoxy-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(6-Phenyl-2-o-tolyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[2-(4-Chloro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(3-Fluoro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[6-Phenyl-2-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[2-(4-Fluoro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(3-Chloro-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(3-Bromo-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(2,6-Diphenyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(3-Methyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[3-(2,4-Difluoro-phenyl)-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(3-Methyl-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(3,6-Diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-[4-(6-Phenyl-3-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[3-(4-Methoxy-phenyl)-2-methyl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[3-(2-Methoxy-pyrimidin-5-yl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[6-Phenyl-3-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-[4-(3-Naphthalen-1-yl-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutylamine;1-{4-[3-(2-Fluoro-5-trifluoromethyl-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[3-(3-Chloro-4-fluoro-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[3-(3-Fluoro-5-isopropoxy-phenyl)-6-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;1-{4-[6-Phenyl-3-(2,3,4-trifluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-cyclobutylamine;3-Amino-3-[4-(2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol;3-Amino-3-[4-(3-bromo-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol;3-Amino-1-methyl-3-[4-(3-methyl-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutanol;3-Amino-1-methyl-3-[4-(6-phenyl-2-o-tolyl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-cyclobutanol;3-Amino-3-{4-[2-(4-fluoro-phenyl)-6-phenyl-pyrazolo[2-(4-fluoro-pheny,5-a]pyrimidin-5-yl]-phenyl}-1-methyl-cyclobutanol;3-Amino-3-[4-(2,6-diphenyl-3-pyridin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol;3-Amino-3-{4-[3-(3-amino-phenyl)-2,6-diphenyl)-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-1-methyl-cyclobutanol;3-Amino-3-[4-(2,6-diphenyl-3-pyrimidin-5-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-phenyl]-1-methyl-cyclobutanol;and3-Amino-3-{4-[3-(2-amino-pyrimidin-5-yl)-2,6-diphenyl-pyrazolo[1,5-a]pyrimidin-5-yl]-phenyl}-1-methyl-cyclobutanol;or a tautomer thereof; or a pharmaceutically acceptable salt orstereoisomer thereof.
 6. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 1. 7. The use of the compoundaccording to claim 1 for the preparation of a medicament useful in thetreatment or prevention of cancer in a mammal in need of such treatment.